RU2158589C2 - Method for minimization of hysterotrophic effect of tamoxyphene and analogs thereof - Google Patents

Abstract

FIELD: pharmaceutical chemistry. SUBSTANCE: invention, in particular, relates to non-steroid compounds of formula II:

(II), wherein R⁴,R⁵,R⁶,R⁷,R⁸ are defined in claims, or pharmaceutically acceptable salt thereof, whose hysterotrophic effect is minimized by simultaneously or successively introducing compound of formula I:

(I), wherein R¹,R²,R³ are defined in claims, or pharmaceutically acceptable salt thereof. Resulting pharmaceutical composition is adequate for treating or preventing mammary gland cancer. EFFECT: enhanced antineoplastic properties and minimized harmful hysterotrophic effect. 11 cl, 1 tbl, 35 ex

Description

является широко известным антиэстрогенным соединением, которое применяется для лечения и профилактики рака молочной железы у млекопитающих. Смотри The Merk Index, 11th Ed., 1430 (1989). Известно, что, хотя тамоксифен действительно эффективен при лечении/профилактике данного заболевания, он вызывает некоторые гистеротрофные эффекты, которые могут быть вредны для пациенток, получающих лечение тамоксифеном. Таким образом, было бы выгодным, если бы было доступно фармацевтическое средство, которое не оказывало бы влияние на антинеопластические полезные свойства, которые обеспечивает тамоксифен, в то же время сводя к минимуму или элиминируя вредный гистеротрофный эффект.Tamoxifen (1-p-dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene) represented by the structural formula

is a widely known anti-estrogenic compound that is used to treat and prevent mammary cancer in the mammary gland. See The Merk Index, 11th Ed., 1430 (1989). It is known that although tamoxifen is indeed effective in the treatment / prophylaxis of this disease, it causes some hysterotrophic effects that may be harmful to patients receiving tamoxifen treatment. Thus, it would be advantageous if a pharmaceutical agent were available that did not affect the antineoplastic benefits that tamoxifen provides, while minimizing or eliminating the harmful hysterotrophic effect.

 Thus, the present invention relates to a method for minimizing the hysterotrophic effect of tamoxifen and certain tamoxifen analogues by the simultaneous or sequential administration of certain naphthyl pharmaceutical agents. Pharmaceutical compositions are also provided.

 SUMMARY OF THE INVENTION

где либо R⁴ является H или низшим алкильным радикалом и R⁵ является низшим алкильным радикалом, либо R⁴ и R⁵ соединены вместе с соседним атомом азота с образованием гетероциклического радикала;
R⁶ является H или низшим алкильным радикалом;
R⁷ является H, галогено, OH, низшим алкильным радикалом или является бута-1,3-диенильным радикалом, который вместе с соседним бензольным кольцом образует нафтильный радикал;
R⁸ является H или OH; и
n равно 2;
или их фармацевтически приемлемых солей, когда указанное соединение формулы II вводят женщине для лечения или профилактики рака молочной железы, который заключается в одновременном или последовательном введении данной женщине соединения формулы I

где R¹ представляет -H, -OH, -O(C₁-C₄ алкил), -OCOC₆H₅, -OCO(C₁-C₆ алкил) или -OSO₂(C₄-C₆ алкил);
R² представляет -H, -OH, -O(C₁-C₄ алкил), -OCOC₆H₅, -OCO(C₁-C₆ алкил) или -OSO₂(C₄-C₆ алкил);
n равен 2 или 3; и
R³ представляет 1-пиперидинил, 1-пирролидинил, метил-1-пирролидинил, диметил-1-пирролидинило, 4-морфолино, диметиламино, диэтиламино или 1-гексаметиленимино;
или его фармацевтически приемлемые соли.The present invention relates to a method for minimizing the hysterotrophic effect of non-steroidal antiestrogenic compounds of formula II

where either R ⁴ is H or a lower alkyl radical and R ⁵ is a lower alkyl radical, or R ⁴ and R ^{5 are} joined together with an adjacent nitrogen atom to form a heterocyclic radical;
R ⁶ is H or a lower alkyl radical;
R ⁷ is H, halo, OH, a lower alkyl radical, or is a buta-1,3-dienyl radical, which together with the adjacent benzene ring forms a naphthyl radical;
R ⁸ is H or OH; and
n is 2;
or their pharmaceutically acceptable salts, when the specified compound of formula II is administered to a woman for the treatment or prevention of breast cancer, which consists in the simultaneous or sequential administration of a woman to the compound of formula I

where R ¹ represents —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl) or —OSO ₂ (C ₄ -C ₆ alkyl);
R ² is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl), or —OSO ₂ (C ₄ -C ₆ alkyl);
n is 2 or 3; and
R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino or 1-hexamethyleneimino;
or its pharmaceutically acceptable salts.

 Also described is a pharmaceutical composition comprising a compound of formula I and a compound of formula II together with a pharmaceutically acceptable carrier, excipient or diluent.

 DETAILED DESCRIPTION OF THE INVENTION

 The present invention relates to the discovery that a particular group of pharmaceutically active naphthyl compounds (compounds of formula I) are useful for minimizing the hysterotrophic effect of non-steroidal antiestrogen compounds of formula II. Formulas I and II are given below.

где R¹ представляет -H, -OH, -O(C₁-C₄ алкил), -OCOC₆H₅, -OCO(C₁-C₆ алкил) или -OSO₂(C₄-C₆ алкил);
R² представляет -H, -OH, -O(C₁-C₄ алкил), -OCOC₆H₅, -OCO(C₁-C₆ алкил) или -OSO₂(C₄-C₆ алкил);
n равен 2 или 3; и
R³ представляет 1-пиперидинил, 1-пирролидинил, метил-1-пирролидинил, диметил-1-пирролидинил, 4-морфолино, диметиламино, диэтиламино или 1-гексаметиленимино; или его фармацевтически приемлемая соль; и

где либо R⁴ представляет H или низшим алкильным радикалом и R⁵ является низшим алкильным радикалом, либо R⁴ и R⁵ соединены вместе с соседним атомом азота с образованием гетероциклического радикала;
R⁶ является H или низшим алкильным радикалом;
R⁷ является H, галогено, OH, низшим алкильным радикалом или является бута-1,3-диенильным радикалом, который вместе с соседним бензольным кольцом образует нафтильный радикал;
R⁸ является H или OH; и
n равно 2;
или его фармацевтически приемлемая соль.

where R ¹ represents —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl) or —OSO ₂ (C ₄ -C ₆ alkyl);
R ² is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl), or —OSO ₂ (C ₄ -C ₆ alkyl);
n is 2 or 3; and
R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino or 1-hexamethyleneimino; or a pharmaceutically acceptable salt thereof; and

where either R ⁴ is H or a lower alkyl radical and R ⁵ is a lower alkyl radical, or R ⁴ and R ^{5 are} joined together with an adjacent nitrogen atom to form a heterocyclic radical;
R ⁶ is H or a lower alkyl radical;
R ⁷ is H, halo, OH, a lower alkyl radical, or is a buta-1,3-dienyl radical, which together with the adjacent benzene ring forms a naphthyl radical;
R ⁸ is H or OH; and
n is 2;
or a pharmaceutically acceptable salt thereof.

Descriptive chemical terms used for formulas I and II have their usual meaning. For example, the term “halogen” includes bromo, chloro, fluoro and iodo. The term "lower alkyl" or "C ₁ -C ₄ alkyl" refers to unbranched and branched aliphatic radicals consisting of 1-4 carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert -butyl. In addition, the term "C ₁ -C ₄ alkoxy" refers to unbranched and branched aliphatic ether radicals consisting of 1-4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert butoxy.

The compounds of formula I, in particular the compound in which each of R ¹ and R ² are each —OH and R ³ is 1-piperidinyl, are nuclear regulatory molecules. These compounds bind to estrogen receptors and are useful in treating various clinical symptoms associated with postmenopausal syndrome, uterine fibroid disease, endometriosis, and proliferation of aortic smooth muscle cells. Indeed, compounds of formula I block the action of estrogen in some cells, but in other types of cells, compounds of formula I activate the same genes that activate estrogen and exhibit the same pharmacological properties (for example, inhibiting osteoporosis caused by estrogen deficiency and lowering serum levels cholesterol). Essentially, the compounds of formula I can be referred to as tissue-selective antiestrogens with mixed agonist-antagonistic properties.

 Although the compounds of formula I and estrogen use and compete for the same receptors, the pharmacological effect of the administration of these two groups of agents cannot be predicted with certainty, and it is individual for each of them.

 Compounds of formula I are prepared according to the methods given below.

 The starting material for one preparation route for the compounds of formula I of the present invention, the compounds of formula VII below, is prepared essentially as described in US Pat. No. 4,230,862, issued October 28, 1980, which is incorporated herein by reference.

где R^1b представляет -H или O(C₁-C₄ алкил); и
Y является метокси или R³-(CH₂)_n-O-, в котором R³ и n определены выше. Предпочтительно, R^1b является метокси, Y является R³-(CH₂)_n-O-, R³ является 1-пиперидинилом и n равно 2.

where R ^1b represents —H or O (C ₁ -C ₄ alkyl); and
Y is methoxy or R ³ - (CH ₂ ) _n —O— wherein R ³ and n are as defined above. Preferably, R ^1b is methoxy, Y is R ³ - (CH ₂ ) _n —O—, R ³ is 1-piperidinyl and n is 2.

где R^1a определяется выше, подвергают взаимодействию ацилирующим агентом, таким как фенилбензоат формулы

где Y определен выше. Реакцию обычно проводят в присутствии умеренно сильного основания, такого как амид натрия, и она протекает при комнатной температуре или ниже.Typically readily available tetralone or a salt thereof of the formula

where R ^{1a as} defined above, is reacted with an acylating agent, such as a phenyl benzoate of the formula

where Y is defined above. The reaction is usually carried out in the presence of a moderately strong base, such as sodium amide, and it proceeds at room temperature or lower.

As for the next step, in one embodiment, the selective compound of formula VII, after being converted to the enolphosphate derivative in situ, is reacted under Grignard conditions with a Grignard reagent of the formula
R ^2b- MgBr
where R ^2b is —H or —O (C ₁ -C ₄ alkyl), to give Formula IIIa below, which are also known in the art (see, for example, US Patent No. 4,230,862 above).

где R^1b, R^2b и Y определены выше, или его фармацевтически приемлемой соли.

where R ^1b , R ^2b and Y are as defined above, or a pharmaceutically acceptable salt thereof.

When Y in the compound of formula III is R ³ - (CH ₂ ) _n —O—, such compounds can be reduced or deprotected as described below. When Y in the compound of formula III is methoxy, one of the synthesis routes shown in Scheme I is used first (see end of description, used first. R ^1b , R ^2b , R ³ and n in Scheme I are defined above.

 Each stage of the synthesis pathways A and B in Scheme I is carried out using methods well known to those skilled in the art.

For example, compounds of formula IIIc are prepared by treating compounds of formula IIIb with pyridine hydrochloride under reflux. If under these conditions R ^1b and / or R ^2b are alkoxy, these groups will be dealkylated to hydroxy groups. The application of this method eliminates the need for a deprotection step of such an alkoxy group at a later stage, if desired.

Alternatively, the methoxy group Y in formula IIIb may be selectively demethylated by treating the compound with an equivalent of sodium thioethoxide in an inert solvent such as N, N-dimethylformamide (DMF) under conditions of moderately elevated temperature ranging from about 80 ^° C. to about 100 ^° C. The progress of this stage can be monitored using conventional chromatographic methods, such as thin layer chromatography (TLC).

When a compound of formula IIIc is obtained, it can be reacted with a compound of formula
R ³ - (CH ₂ ) _n -Q
wherein R ^{3 is as} defined above and Q is bromo or preferably chloro to give compounds of formula IIId. This reaction is depicted as the last step of path A in Scheme I.

Under normal alkylation conditions, this reaction will proceed along each of the hydroxy groups that may be present in the molecule of formula IIIc. However, by carrying out the reaction in the presence of an excess of finely divided powdered potassium carbonate, and using an equivalent to a small excess of the Q- (CH ₂ ) -R ³ reagent, selective alkylation at the 4-hydroxybenzoyl group can be achieved.

To obtain compounds of formula IIIe, as shown in path B of Scheme I, the compound of formula IIIc is reacted with an excess of an alkylating agent of the formula
Z- (CH ₂ ) _n -Z '
where each of Z and Z 'represent the same or different leaving groups in an alkali solution.

 Suitable leaving groups include, for example, sulfonates such as methanesulfonate, 4-bromosulfonate, toluenesulfonate, ethanesulfonate, isopropanesulfonate, 4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate, 2-chlorobenzenesulfonate and the like, halogens and the like, halogens and the like , and other related groups. The preferred alkylating agent is 1,2-dibromoethane, and at least 2 equivalents, preferably more than 2 equivalents of 1,2-dibromoethane, are used per equivalent of substrate.

 A preferred alkaline solution for this alkylation reaction consists of potassium carbonate in an inert solvent such as methyl ethyl ketone (MEK) or DMF. In this solution, the 4-hydroxy group of the benzoyl radical of the compound of formula IIId exists in the form of a phenoxide ion, which replaces one of the leaving groups of the alkylating agent.

 This reaction proceeds best when the alkali solution containing the reagents and reagents is brought to a boil and left to complete the reaction. When using IEC as a preferred solvent, the reaction time varies from about 6 hours to about 20 hours.

The reaction product in this step, the compound of formula IIIe, is then reacted with 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine or 1-hexamethyleneimine in the usual manner to give compounds formula IIId. Preferably, the piperidine hydrochloride salt is reacted with a compound of formula IIIe in an inert solvent, such as anhydrous DMF, and heated to a temperature in the range of from about 60 ^° C. to about 110 ^° C. When the mixture is heated to a preferred temperature of about 90 ^° C., the reaction proceeds for only about 30 minutes to about 1 hour. However, changes in the reaction conditions will affect the time it takes for the reaction to complete. Of course, the progress of this stage of the reaction can be monitored using conventional chromatographic methods.

 Compounds of formula IIId are the starting material for one process for the preparation of pharmaceutically active compounds of formula Ia, as shown in Scheme II (see end of description).

where R ^1a , R ^2a , R ³ and n are defined as above.

 In Scheme II, a compound of formula IIId or a salt thereof is added to a suitable solvent and reacted with a reducing agent, such as, for example, lithium aluminum hydride (PAH). Although a free base of a compound of formula IIId can be used in this reaction, often adding an acid, preferably a hydrochloric acid salt, is more convenient.

 The amount of reducing agent used in this reaction is an amount sufficient to reduce the carbonyl group of the compound of formula IIId to form carbinol compounds of formula IV. An arbitrary excess of reducing agent per equivalent of substrate is usually used.

 Suitable solvents include any solvent or mixture of solvents that will remain inert under reduction conditions. Suitable solvents include diethyl ether, dioxane and tetrahydrofuran (THF). An anhydrous form of these solvents is preferred, and anhydrous THF is particularly preferred.

The temperature used at this stage is that which will be sufficient for the reaction to proceed completely. An ambient temperature in the range of from about 17 ^° C. to about 25 ^° C. is usually sufficient.

 The time interval for this stage is the period necessary for the reaction to proceed. Typically, this reaction proceeds from about 1 hour to about 20 hours. The optimal time can be determined by monitoring the progress of the reaction using widespread chromatographic methods.

 Carbinol products at this stage of the reaction (compounds of formula IV) are isolated essentially by the method described in example 7 below and are used in the methods described here.

When a carbinol of formula IV is obtained, such a compound is added to an inert solvent, such as, for example, ethyl acetate, followed by the addition of a strong protic acid, such as hydrochloric acid, to give compounds of the formula Ia. This reaction usually proceeds at an ambient temperature of from about 17 ^o C to about 25 ^o C and usually ends in only about a few minutes to about 1 hour. Crystallization of the final product is carried out according to standard methods, essentially, as described in example 1, below.

 Dealkylation / deprotection of terminal protected hydroxy groups may be carried out before the preparation of compounds of formula IV, before the preparation of compounds of formula Ia, or after the preparation of protected compounds of formula Ia, by methods known to those skilled in the art. However, dealkylation of the protected compound of formula Ia after preparation is preferred.

The reaction shown in Scheme II provides pharmaceutically active compounds of formula Ia in which each of R ^1a and R ^2a is hydrogen or C ₁ -C ₄ alkoxy. Preferred compounds of formula Ia are those wherein R ^1a and R ^2a each are methoxy or R ^1a and R ^2a each are hydroxy, R ³ is piperidinyl and n is 2. These preferred compounds, the latter being particularly preferred, are also , like other compounds of formula Ia, can be used as pharmaceuticals or can further be used for other compounds of formula I, which are also applicable to the practice of the methods of the present invention.

As an alternative to the reactions shown in Scheme II, a one-step process can be used to prepare the compounds of formula Ia of the present invention, which consists in reducing the ketone of formula V below. More specifically, when R ^1a and / or R ^2a is —O (C ₁ -C ₄ alkyl), these hydroxy protecting groups may be removed prior to applying the present new process or, optionally, may be removed in situ after the present one-step reduction process. In addition to this, the product of this process, which may contain 1 or 2 unprotected or protected hydroxyl radicals, can optionally be converted to a salt by known methods or as described herein.

где R^1a, R^2a, R³ и n определены выше, или его соль подвергают взаимодействию с восстановителем, таким как литийалюминийгидрид или Red-Al® [бис(2-метоксиэтоксиалюминийгидрид)натрия] в присутствии растворителя с температурой кипения в интервале от около 150^oC до около 200^oC.In this method, the compound of formula V

where R ^1a , R ^2a , R ³ and n are defined above, or its salt is reacted with a reducing agent such as lithium aluminum hydride or Red-Al® [sodium bis (2-methoxyethoxy aluminum hydride) in the presence of a solvent with a boiling point in the range of about 150 ^o C to about 200 ^o C.

где R^1b и R^2b определены выше, затем деметилируют, как описано выше, и алкилируют соединением формулы
R³-(CH₂)_n-Q
где R³ определено выше, по вышеописанным способам.Compounds of formula V are prepared by reacting a compound of formula IIIb (as described above) with about 2 equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDC) in the presence of an inert solvent or mixture of solvents, such as, for example , dioxane, dichloromethane, toluene, dichloroethane or benzene. The reaction mixture is usually refluxed for about 1 to 2 hours and then allowed to mix at ambient temperature for about 36 to about 72 hours. The resulting compound of formula VI

where R ^1b and R ^{2b are as} defined above, then demethylated as described above and alkylated by a compound of the formula
R ³ - (CH ₂ ) _n -Q
where R ³ defined above, by the above methods.

 In this reducing reaction, the amount of reducing agent used in this reaction is an amount sufficient to reduce the carbonyl group of the compound of formula V to give the compound of formula Ia. An arbitrary excess of reducing agent per equivalent of substrate is usually used.

The requirements for the solvent used in the process is the presence of a relatively high boiling point in the range of from about 150 ^° C to about 200 ^° C, which solvents have, such as, for example, n-propylbenzene, diglyme (1,1'-hydroxybis [2 methoxyethane]) and anisole. Of these, n-propylbenzene is the preferred solvent for compounds of formula V when R ^1a and / or R ^2a are —OCH ₃ and —C ₆ H ₄ -4′-O (C ₁ -C ₄ alkyl). Red-Al, used both as a solvent and as a reducing agent, is preferred when R ^1a is —OH and / or R ^2a is —C ₆ H ₄ -4′-OH.

 The temperature used in this reaction is that which is sufficient for the reaction to proceed to completion. Preferably, the reaction mixture is refluxed for about 15 minutes to about 6 hours, allowed to cool to ambient temperature and treated by conventional methods [see, for example, Fieser and Fieser, Reagents for Organic Synthesis, Volume 1, page 584 ( 1968)] and, as described hereinafter in the examples. The optimal time for this reaction, from about 10 minutes to about 1 hour, can be determined by monitoring the progress of the reaction by standard methods.

 The products of formula Ia in a one-step reaction are isolated essentially as described in Example 2 below. Preferred compounds of formula Ia in this reaction are the same compounds as the preferred compounds of formula Ia described above, and they can be used as pharmaceutically active agents in the methods described herein, or they can be used to obtain other compounds of formula I, which also applicable in the present methods.

For example, when R ^1a and / or R ^2a in a compound of formula I are C ₁ -C ₄ alkyl hydroxy protecting groups (thus not being dealkylated as suggested in one embodiment of Scheme I), such groups can be removed by conventional dealkylation methods, such as described in example 2 below, with the preparation of a particularly preferred compound of formula Ia.

Other preferred compounds of formula I are prepared by replacing the newly formed R ^1a and / or R ^2a hydroxy groups of a compound of formula Ia with a radical of the formula —O — CO— (C ₁ -C ₆ alkyl) or —O — SO ₂ - (C ₄ -C ₆ alkyl ) by well-known methods. See, for example, U.S. Patent No. 4,358,593.

For example, when a —O — CO— (C ₁ -C ₆ alkyl) group is desired, the dihydroxy compound of formula Ia is reacted with an agent such as acyl chloride, bromide, cyanide or azide or with a suitable anhydride or mixed anhydride. The reactions are conveniently carried out in a basic solvent, such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent, such as triethylamine, tributylamine, methylpiperidine and the like. The reaction can also be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethyl sulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone and the like, to which at least one equivalent of an acid acceptor is added (with the exceptions indicated below), such as a tertiary amine. Acylation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine can be used if desired. See, for example, Haslam et al., Tetrahedron, 36: 2409-2433 (1980).

The acylation reactions that give the above terminal R ¹ and R ² groups of the compounds of formula I are carried out at moderate temperatures ranging from about -25 ^° C to about 100 ^° C, often in an inert atmosphere such as a nitrogen gas atmosphere. However, usually the ambient temperature is sufficient for the reaction to proceed.

 Such acylations of these hydroxy groups can also be carried out by acid-catalyzed reactions, suitable carboxylic acids in inert organic solvents or by heating. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid and the like are used.

The above R ¹ and / or R ² groups in the compounds of formula I can also be obtained by forming an active ester of a suitable acid, such as esters formed by known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide and 1- hydroxybenzotriazole. See, for example, Bull. Chem. Soc. Japan, 38: 1979 (1965) and Chem. Ber., 788 and 2024 (1970).

Each of the above methods, which leads to —O — CO— (C ₁ -C ₆ alkyl) radicals, is carried out in solvents, as discussed above. Those methods in which no acid product is formed during the reaction, of course, do not require the use of an acid acceptor in the reaction mixture.

When a compound of formula I is desired in which R ^1a and / or R ^{2a, a} group of a compound of formula Ia is converted to a group of the formula —O — SO ₂ (C ₄ –C ₆ alkyl), (20 ml) and the reaction mixture is refluxed. Volatile components were evaporated in vacuo and the residue was purified by silica gel column chromatography (200 g) using dichloromethane and a mixture of ethanol and 25% NH ₃ (aq) (9: 1) as an eluent (gradient from 0% to 10%) . This gives 0.30 g of 3-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine.

¹ H NMR (CDCl ₃ ) δ 2.05-2.15 (m, 1H); 2.64-2.75 (m, 1H); 2.95-3.05 (m, 1H); 3.44 (dd, 1H); 3.48-3.52 (m, 1H); 7.13 (d, 1H, J = 9 Hz); 7.49 (t, 1H, J = 9 Hz); 7.56 (t, 1H, J = 9 Hz); 7.60 (br s, 1H); 7.75 (d, 1H, J = 9 Hz); 7.85 (d, 1H, J = 9 Hz); 8.07 (d, 1H, J = 9 Hz).

 (1,1-Dimethyl-2- (4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-ylcarbamoyl) ethyl) carbamic acid tert-butyl ester.

 To a solution of 3-tert-butyloxycarbonylamino-3-methylbutanoic acid (0.26 g, 1.2 mmol) in DMF (15 ml) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.24 g, 1 , 2 mmol). After 15 minutes at room temperature, 3-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine (0.25 g, 1.1 mmol) was added and the reaction the mixture was stirred for 6 hours. Water (80 ml) was added and the solution was extracted with ethyl acetate (30 ml). The organic phase is washed with sodium bicarbonate, iodide, nitrogen, sulfur, phosphoric, hypophosphoric and the like. Salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids can also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate , butyn-1,4-dioate, hexin-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxy maleate, malonate, mandelate, mesylate , nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, sulfate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenyl propionate, salicylate, sebacinate, succinate, superate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzene sulfonate, sulfonate, sulfonate, 2-b-sulfonate methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylene sulfonate, tartrate and the like. A preferred salt is a hydrochloric acid salt.

 Pharmaceutically acceptable acid addition salts are usually prepared by reacting a compound of formula I with an equimolar or excess acid. The reagents are usually mixed in a common solvent, such as diethyl ether or ethyl acetate. Salt usually precipitates from the solution within about one hour to 10 days and can be isolated by filtration, or the solvent can be removed using widely accepted methods.

 Pharmaceutically acceptable salts typically have improved solubility characteristics compared to the compound of which they are derivatives, and thus are often better suited to be prepared in the form of liquids or emulsions.

 Compounds of formula II used in the methods and pharmaceutical compositions of the present invention are prepared by known methods, such as those described in US Pat. No. 4,623,600, which is incorporated herein by reference. Pharmaceutically acceptable acid addition salts of the compounds of formula II are prepared as described above.

A preferred compound of formula II in which each of R ⁴ and R ⁵ is methyl, R ⁶ is ethyl, each of R ⁷ and R ⁸ is H, and n is 2, is known in the art as tamoxifen. Tamoxifen and its analogues of formula II are antiestrogenic compounds, and tamoxifen is mainly used to treat breast cancer in women. In addition to this well-known activity in the art, it is also widely recognized that tamoxifen can cause certain side effects, in particular endometrial cancer, which can potentially be life threatening. [see, for example, Fisher, B., et al., JNCI, 86 (7): 527-537 (1994)].

On the one hand, the present invention relates to a method for minimizing the hysterotrophic effect of a non-steroidal antiestrogenic compound of formula II, in particular tamoxifen, by administering a compound of formula I, in particular a compound in which each of R ¹ and R ² is —OH and R ³ is 1 -piperidinyl, a woman undergoing treatment with a compound of formula II for the treatment or prevention of breast cancer. In this context, “hysterotrophic effect” means the proliferation of uterine epithelial cells, which can often be a side effect of the administration of tamoxifen to women. It seems that this hysterotrophic effect is directly involved in the development of endometrial cancer.

The administration of a compound of formula I, in particular a compound in which each of R ¹ and R ² is —OH and R ³ is 1-piperidinyl, minimizes the hysterotrophic effect of the simultaneously or sequentially administered compound of formula II, in particular tamoxifen, without affecting the action of the compound formula II in relation to breast cancer. The term "minimization" or its derivatives includes partial or complete inhibition of tamoxifen-induced hysterotrophic action on uterine epithelial cells.

 To treat breast cancer in humans, tamoxifen or another compound of formula II may be administered, alone or in combination with other chemotherapeutic agents and / or radiotherapy, as an adjuvant to surgery or, under certain circumstances, may be considered for use as chemosuppressive chemoprophylactic agent. Since each of these administration regimens may present different degrees of risk of developing hysterotrophic side effects, the attending physician can best decide whether to administer a compound of formula I simultaneously or sequentially with respect to the administration of a compound of formula II.

 When administered sequentially, the pharmaceutical compositions of the compounds of formulas I and II are prepared by the methods described herein.

With the simultaneous administration of the compounds of formula I and formula II can be obtained in the form of pharmaceutical formulations by the above-mentioned known methods and administered in separate doses. Alternatively, they can be combined to form a pharmaceutical composition of the present invention, which includes an effective amount of a compound of formula I and an effective amount of a compound of formula II, preferably a compound of formula I, in which each of R ¹ and R ² is —OH, and R ³ is piperidinyl and tamoxifen, respectively, together with a pharmaceutically acceptable carrier, excipient or diluent.

 As used above and throughout this description, the term "effective amount" means that the dosage of the active (s) compound (s) is sufficient to provide therapeutic treatment for a particular clinical symptom.

 The term “active compound”, as used throughout this specification, refers to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and / or a compound of formula II or a pharmaceutically acceptable salt thereof.

 For therapeutic treatment of a particular symptom, a compound of formula I, as such, with or without a compound of formula II, may be administered or may be mixed and formulated into pharmaceutical compositions in unit dosage forms for parenteral, transdermal, rectal nasal, intravenous or predominantly oral administration . Such pharmaceutical compositions are prepared by methods well known in the art, and they contain compounds of formula I, optionally including compounds of formula II. In preparing the compositions of the present invention, the active ingredients are usually mixed with a carrier, or diluted with a carrier, or enclosed in a carrier, which may be in the form of a capsule, sachet, paper or other container. When the carrier acts as a diluent, it may be a solid, semi-solid or liquid material that acts as a solvent, excipient or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, starch tablets, elixirs, emulsions, solutions, syrups, suspensions, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

 In addition, the compounds of the present composition, in particular the compounds of formula I, are well suited for the preparation of sustained release dosage forms and the like. The compositions can be formulated so that they release the active ingredients only or preferably at a particular physiological location, possibly over a period of time. Coating, shells and protective matrices can be made, for example, from polymeric substances or waxes.

 Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, calcium salicylate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth, gelatin and methyl syrup, gelatin, syrup propylhydroxybenzoates, talc, magnesium stearate, water and mineral oil. The compositions may further comprise lubricating agents, wetting agents, emulsifiers and suspending agents, preservatives, sweeteners or flavorings. Compositions can be formulated to provide quick, sustained or delayed release of the active ingredient (s) after administration to a patient by methods well known in the art. For oral administration, the compounds, optionally including a component of the second compound, can be mixed with carriers and diluents, compressed into tablets, or enclosed in gelatin capsules. The mixtures may optionally be dissolved in liquids, such as a 10% aqueous glucose solution, isotonic saline, sterile water and the like, and administered intravenously or by injection.

 The compositions are preferably formulated in unit dosage form, each dose containing from about 1 to about 500 mg, and more often from about 5 to about 300 mg, of the active ingredient (s). The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for humans, each unit containing a predetermined amount of active ingredients, calculated to produce the desired therapeutic effect in combination with the desired pharmaceutically acceptable carrier. By “pharmaceutically acceptable” is meant that the carrier, diluent or excipient must be with the other ingredients of the composition and should not be harmful to its recipient.

 The compounds of formula I, alone or in combination with a pharmaceutical agent of the present invention, are usually administered in the form of a conventional preparation. The following formulation examples are illustrative only and should not be construed as limiting the scope of the present invention.

 Compositions 1-5 cm (at the end of the description).

 Specific formulations 1-5 may be changed in accordance with the foreseeable reasonable variations.

 Tablet preparations are prepared using the following ingredients (see formulations 6, 7 at the end of the description).

 To form a tablet, the components are mixed and pressed.

 Alternatively, tablets, each of which contains 25-1000 mg of the compound of formula I, are prepared as follows (see composition 7 at the end of the description).

The compound of formula I, starch and cellulose are passed through a No. 45 mesh US sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the obtained powders, which are then passed through a No. 14 mesh US sieve. The granules thus obtained are dried at a temperature of 50-60 ^° C. and passed through a No. 18 mesh US sieve. Sodium carboxymethyl starch, magnesium stearate and talc previously passed through a No. 60 sieve US mesh is then added to the granules, which, after mixing, are compressed using a tabletting apparatus, which allows tablets to be obtained.

 Suspensions, each of which contains 25-1000 mg of the drug in a dose of 5 ml, are prepared as follows (see composition 8 at the end of the description).

 The active ingredient is passed through a No. 45 mesh U.S. sieve. and mixed with sodium carboxymethyl cellulose and syrup to obtain a uniform paste. With stirring, a solution of benzoic acid, flavor and color diluted with a large amount of water are added. Then add water in an amount sufficient to achieve the desired volume (see composition 9, 10 at the end of the description).

 The specific dose of a compound of formula I required to minimize the hysterotrophic effect of the non-steroidal antiestrogenic compound of formula II of this invention will depend on the severity of the condition, route of administration, and related factors that are evaluated by the attending physician. Typically, acceptable and effective daily doses of a compound of formula I will be from about 0.1 mg to about 1000 mg / day, and more typically from about 50 mg to about 600 mg / day. Such doses are administered to a subject in need of treatment from one to three times daily or more often, as necessary to effectively treat the symptom present. Generally, it is preferable to administer a compound of formula I in the form of an acid addition salt, which is usually used when administering drugs containing a basic group such as a piperidine ring. It is also preferable to administer such a compound orally.

 The compounds of formula II, in particular tamoxifen, are administered for the treatment of breast cancer in doses and in lines that are consistent with those well known in the art. However, it is preferable to introduce a substantial excess of the compound of formula I with respect to the compound of formula II.

 The following examples are provided to further illustrate the preparation of the compounds of the present invention. You should not think that the scope of the invention is limited to any of the following example.

 NMR data for the following examples was obtained on a 300 MHz GE NMR spectrometer and anhydrous d-6 DMSO was used as the solvent, unless otherwise indicated.

 Getting 1.

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] (4-methoxyphenyl) methanone.

К суспензии гидрида натрия (12,75 г в 60% масляной дисперсии, предварительно промытой гексаном, 0,32 моль), перемешиваемой в тетрагидрофуране (ТГФ) (650 мл) при 0^oC, добавляли раствор (3,4-дигидро-2-гидрокси-6-метокси-1-нафталинил)(4-метоксифенил)метанона (90,0 г, 0,29 ммоль; (Смотри, например, патент США N 4230862) и дифенилхлорфосфата (77,8 г, 0,29 ммоль) в ТГФ (750 мл). Скорость добавления была такой, чтобы температура реакции поддерживалась ниже 8^oC. После перемешивания в течение 3 часов при 0^oC по каплям добавляли 4-MeOC₆H₄MgBr (1,5 эквивалента 0,064 г/мл раствора в ТГФ) и полученной смеси дали постепенно нагреться до комнатной температуры. Через 12 часов раствор гасили добавлением холодного водного хлорида аммония. Органическую часть отделяли от смеси и водную часть экстрагировали этилацетатом. Объединенные органические экстракты сушили (сульфат натрия), фильтровали и концентрировали. К полученному маслу добавляли ацетонитрил (1 л) до образования осадка. Твердые продукты удаляли фильтрованием и фильтрат концентрировали, что давало масло, которое очищали методом флэш-хроматографии (силикагель, метиленхлорид). Желаемый продукт последовательно очищали кристаллизацией из метанола с получением 96,7 г (83%) указанного в заголовке соединения в виде желтого кристаллического твердого продукта: т.пл. = 172-173^oC; ¹H ЯМР (ДМСО-d₆) δ 7,75 (д, J = 8,7 Гц, 2H), 7,16 (д, J = 8,6 Гц, 2H), 6,60-6,90 (сложный, 7H), 3,74 (с, 3H), 3,71 (с, 3H), 3,64 (с, 3H), 2,96 (м, 2H), 2,96 (м, 2H); МС (FD) m/e 400 (M+).

To a suspension of sodium hydride (12.75 g in a 60% oil dispersion, pre-washed with hexane, 0.32 mol), stirred in tetrahydrofuran (THF) (650 ml) at 0 ^° C., a solution of (3,4-dihydro-2 -hydroxy-6-methoxy-1-naphthalenyl) (4-methoxyphenyl) methanone (90.0 g, 0.29 mmol; (see, for example, US Pat. No. 4,230,862) and diphenyl chlorophosphate (77.8 g, 0.29 mmol ) in THF (750 ml). The rate of addition was such that the reaction temperature was kept below 8 ^° C. After stirring for 3 hours at 0 ^° C., 4-MeOC ₆ H ₄ MgBr was added dropwise (1.5 equivalents of 0.064 g / ml of solution in THF) and obtained the mixture was allowed to gradually warm to room temperature. After 12 hours, the solution was quenched by addition of cold aqueous ammonium chloride. The organic portion was separated from the mixture and the aqueous portion was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate), filtered and concentrated. Acetonitrile was added to the resulting oil ( 1 L) until a precipitate formed, the solids were removed by filtration, and the filtrate was concentrated to give an oil which was purified by flash chromatography (silica gel, methylene chloride). The desired product was subsequently purified by crystallization from methanol to give 96.7 g (83%) of the title compound as a yellow crystalline solid: mp. = 172-173 ^o C; ¹ H NMR (DMSO-d ₆ ) δ 7.75 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 6.60-6.90 ( complex, 7H), 3.74 (s, 3H), 3.71 (s, 3H), 3.64 (s, 3H), 2.96 (m, 2H), 2.96 (m, 2H); MS (FD) m / e 400 (M +).

 Getting 2.

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] (4-hydroxyphenyl) methanone.

7,74 (м, 2H), 7,16 (м, 2H), 6,85 (д, J = 8,0 Гц, 1H), 6,77 (с, 1H), 6,65 (м, 5H), 6,11 (с, 1H), 3,78 (с, 3H), 3,69 (с, 3H), 3,00 (м, 2H), 2,77 (м, 2H); ¹³C-ЯМР (75 МГц, CDCl₃) δ 201,1, 162,4, 159,7, 159,6, 137,5, 137,2, 134,6, 134,2, 133,3, 130,6, 129,6, 127,6, 127,2, 116,5, 114,7, 114,5, 112,3, 56,2, 56,0, 30,7, 29,6; Анал. расч. для: C 77,70; H 5,74. Найдено C 77,46; H 5,91. МС (FD) m/e 386 (M+); ИК (хлороформ) 3400,94, 1641,63, 1601,12 см^-1.δ
To a solution of lithium ethanethiol [prepared by adding n-BuLi (87.8 ml of a 1.6 M solution in hexane, 140 mmol) to a solution of ethanethiol (12.1 ml, 164 mmol), stirred at 0 ^° C. in ethyl ether (400 ml ) followed by short stirring and concentration], stirred in dimethylformamide (400 ml), the product was obtained to obtain 1 (46.7 g, 117 mmol). The mixture was then heated at 100 ^o C. After 1 hour, the reaction was concentrated, the resulting brown oil was dissolved in chloroform. This solution was extracted with aqueous ammonium chloride. The aqueous portion was treated with 1N hydrochloric acid until a pH of 5 was obtained, and sequentially extracted with chloroform. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated. The resulting brown oil was purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to give 30.0 g (66%) of the title product as a yellow oil: ¹ H-NMR (300 MHz, CDCl ₃ )

7.74 (m, 2H), 7.16 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.77 (s, 1H), 6.65 (m, 5H ), 6.11 (s, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 3.00 (m, 2H), 2.77 (m, 2H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ 201.1, 162.4, 159.7, 159.6, 137.5, 137.2, 134.6, 134.2, 133.3, 130, 6, 129.6, 127.6, 127.2, 116.5, 114.7, 114.5, 112.3, 56.2, 56.0, 30.7, 29.6; Anal calc. for: C 77.70; H 5.74. Found C, 77.46; H 5.91. MS (FD) m / e 386 (M +); IR (chloroform) 3400.94, 1641.63, 1601.12 cm ^-1 .

 Getting 3.

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] (4- [2- (1-piperidinyl) ethoxy] phenyl] methanone.

7,72 (д, J = 8,0 Гц, 1H), 7,15 (д, J = 10 Гц, 3H), 6,87 (д, J = 11 Гц, 3H), 6,72 (д, J = 8 Гц, 2H), 6,62 (с, 2H), 4,05 (м, 2H), 3,69 (с, 3H), 3,63 (с, 3H), 2,95 (м, 2H), 2,62 (м, 4H), 2,38 (м, 4H), 1,44 (м, 4H), 1,33 (м, 2H); ¹³C-ЯМР (75 МГц, ДМСО-d₆) δ 197,2, 168,22, 168,18, 162,3, 158,4, 158,3, 136,4, 134,9, 133,0, 131,3, 129,6, 128,6, 125,9, 125,4, 114,4, 113,7, 113,6, 113,4, 111,5, 65,7, 62,5, 57,0, 55,0, 54,9, 54,1, 29,1, 28,0, 25,4, 23,7; Анал. расч. для: C 77,24; H 7,09; N 2,81. Получ: C 77,44; H 7,13; N 2,75. МС (FD) m/e 497 (M+); ИК (хлороформ) 1672,5 см^-1.δ
To a solution of the product of Preparation 2 (36 g, 93 mmol) stirred in dimethylformamide (DMF; 1 L) was added potassium iodide (30 mg, 0.18 mmol) followed by potassium carbonate (64.2 g, 465 mmol) and 1- (2-chloroethyl) piperidine monohydrochloride (18.9 g, 102 mmol). The reaction mixture was stirred at ambient temperature overnight, then concentrated and the resulting oil was dissolved in chloroform. This solution was washed thoroughly with water, brine, dried (sodium sulfate), filtered and concentrated. The resulting oil was purified by flash chromatography (silica gel, methanol / chloroform gradient) to give 43 g (93%) of the title product as a yellow foam: ¹ H-NMR (300 MHz, DMSO-d ₆ )

7.72 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 10 Hz, 3H), 6.87 (d, J = 11 Hz, 3H), 6.72 (d, J = 8 Hz, 2H), 6.62 (s, 2H), 4.05 (m, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 2.95 (m, 2H), 2.62 (m, 4H), 2.38 (m, 4H), 1.44 (m, 4H), 1.33 (m, 2H); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) δ 197.2, 168.22, 168.18, 162.3, 158.4, 158.3, 136.4, 134.9, 133.0, 131.3, 129.6, 128.6, 125.9, 125.4, 114.4, 113.7, 113.6, 113.4, 111.5, 65.7, 62.5, 57, 0, 55.0, 54.9, 54.1, 29.1, 28.0, 25.4, 23.7; Anal calc. for: C 77.24; H 7.09; N, 2.81. Receive: C 77.44; H 7.13; N, 2.75. MS (FD) m / e 497 (M +); IR (chloroform) 1672.5 cm ^-1 .

 Example 1

 [2- (4-Methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methane hydrochloride.

К суспензии литийалюминийгидрида (3,80 г, 94,8 ммоль), перемешиваемой при 0^oC в сухом ТГФ (100 мл), медленно добавляли раствор продукта по получению 3 (23,6 г, 47,4 ммоль) в ТГФ (50 мл) в течение 45-минутного промежутка времени. Реакционную смесь оставляли перемешиваться при температуре окружающей среды в течение 14 часов, охлаждали до 0^oC и осторожно гасили водой (5 мл). К данному раствору по каплям добавляли гидроксид натрия (15 мл 15% по массе водного раствора) с последующим добавлением воды (5 мл). Смесь перемешивали в течение 0,5 часа, фильтровали и твердые вещества тщательно промывали этилацетатом. Фильтрат затем концентрировали, что давало 21 г (89%) промежуточного продукта (карбинола) в виде белой пены, который затем использовали без дальнейшей очистки. К промежуточному продукту (23,6 г, 47,2 ммоль), перемешиваемому при температуре окружающей среды в этилацетате (100 мл), добавляли соляную кислоту [100 мл насыщенного этилацетатного раствора]. Осадок непосредственно образовывался в течение концентрирования смеси. Полученное твердое вещество перекристаллизовывали из метанола, что давало 19,4 г (79%) указанного в заголовке продукта в виде белого кристаллического твердого вещества: ¹H-ЯМР (300 МГц, ДМСО-d₆) δ 10,54 (ушир.с, 1H), 7,72-7,80 (сложный, 2H), 7,34-7,38 (сложный, 2H), 7,23 (д, J = 8,5 Гц, 2H), 7,08 (дд, J = 8,4, 2,3 Гц, 1H), 6,80-6,96 (сложный, 6H), 4,30 (ушир.с, 4H), 3,85 (с, 3H), 3,76 (с, 3H), 3,37-3,45 (сложный, 4H), 2,90-2,99 (м, 2H), 1,61-1,82 (сложный, 5H), 1,32-1,39 (м, 1H); МС (FD) m/e 481 (M⁺-соляная кислота); Анал. расч. для: C 74,19; H 7,00; N 2,70. Найдено: C 74,28; H 7,10; N 2,66.

To a suspension of lithium aluminum hydride (3.80 g, 94.8 mmol) stirred at 0 ^° C. in dry THF (100 ml) was slowly added a solution of the product to obtain 3 (23.6 g, 47.4 mmol) in THF (50 ml) for a 45-minute period of time. The reaction mixture was allowed to stir at ambient temperature for 14 hours, cooled to 0 ^° C. and carefully quenched with water (5 ml). Sodium hydroxide (15 ml of a 15% by weight aqueous solution) was added dropwise to this solution, followed by the addition of water (5 ml). The mixture was stirred for 0.5 hours, filtered and the solids washed thoroughly with ethyl acetate. The filtrate was then concentrated, giving 21 g (89%) of the intermediate product (carbinol) as a white foam, which was then used without further purification. To the intermediate (23.6 g, 47.2 mmol) stirred at ambient temperature in ethyl acetate (100 ml) was added hydrochloric acid [100 ml of a saturated ethyl acetate solution]. A precipitate formed directly during concentration of the mixture. The resulting solid was recrystallized from methanol to give 19.4 g (79%) of the title product as a white crystalline solid: ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 10.54 (br s, 1H), 7.72-7.80 (complex, 2H), 7.34-7.38 (complex, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.08 (dd , J = 8.4, 2.3 Hz, 1H), 6.80-6.96 (complex, 6H), 4.30 (br s, 4H), 3.85 (s, 3H), 3, 76 (s, 3H), 3.37-3.45 (complex, 4H), 2.90-2.99 (m, 2H), 1.61-1.82 (complex, 5H), 1.32- 1.39 (m, 1H); MS (FD) m / e 481 (M ⁺ hydrochloric acid); Anal calc. for: C 74.19; H 7.00; N, 2.70. Found: C, 74.28; H 7.10; N 2.66.

 Example 2

 [2- (4-Hydroxyphenyl) -6-hydroxy-naphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methane hydrochloride.

К раствору продукта по примеру 1 (5,0 г, 9,6 ммоль), перемешиваемому в 1,2-дихлорэтане (50 мл) при комнатной температуре, добавляли трихлорид бора (20 мл, 234 ммоль). Полученную темно-пурпурную реакцию оставляли перемешиваться при температуре окружающей среды в течение ночи, затем охлаждали до 0^oC. Затем осторожно по каплям добавляли метанол (50 мл) в течение 2-часового промежутка времени (осторожно: выделение газа), причем в течение этого времени образовывался осадок. Твердое вещество отфильтровывали, промывали холодным метанолом и затем диэтиловым эфиром. Перекристаллизация из метанола давала продукт в виде белого порошка: ¹H-ЯМР (300 МГц, ДМСО-d₆) δ 10,38 (ушир. с, 0,5H), 9,74 (с, 1H), 9,52 (с, 1H), 7,61-7,68 (сложный, 2H), 7,28 (д, J = 8,3 Гц, 1H), 7,08-7,14 (сложный, 3H), 6,99 (дд, J = 9,1, 2,4 Гц, 1H), 6,75-6,91 (сложный, 6H), 4,28-4,31 (сложный, 4H), 3,34-3,45 (сложный, 4H), 2,95 (м, 1H), 1,63-1,75 (сложный, 5H), 1,35 (м, 1H); МС (FD) m/e 454 (M⁺-соляная кислота); Анал. расч. для: C 73,53; H 6,58; N 2,86. Найдено: C 73,48; H 6,57; N 3,01.

To a solution of the product of Example 1 (5.0 g, 9.6 mmol) stirred in 1,2-dichloroethane (50 ml) at room temperature was added boron trichloride (20 ml, 234 mmol). The resulting dark purple reaction was allowed to stir at ambient temperature overnight, then cooled to 0 ^° C. Then methanol (50 ml) was carefully added dropwise over a 2-hour period (caution: gas evolution), during which time a precipitate formed. The solid was filtered off, washed with cold methanol and then with diethyl ether. Recrystallization from methanol gave the product as a white powder: ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 10.38 (br s, 0.5H), 9.74 (s, 1H), 9.52 ( s, 1H), 7.61-7.68 (complex, 2H), 7.28 (d, J = 8.3 Hz, 1H), 7.08-7.14 (complex, 3H), 6.99 (dd, J = 9.1, 2.4 Hz, 1H), 6.75-6.91 (complex, 6H), 4.28-4.31 (complex, 4H), 3.34-3.45 (complex, 4H), 2.95 (m, 1H), 1.63-1.75 (complex, 5H), 1.35 (m, 1H); MS (FD) m / e 454 (M ⁺ hydrochloric acid); Anal calc. for: C 73.53; H 6.58; N, 2.86. Found: C, 73.48; H 6.57; N, 3.01.

 Example 3

 [2- (4-Benzoyloxyphenyl) -6-benzoyloxynaphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methane.

К суспензии продукта по примеру 2 (4,1 г, 8,4 ммоль), перемешиваемого в ТГФ (200 мл), добавляли N,N-диметиламинопиридин (10 мг, в качестве катализатора). Смесь охлаждали до 0^oC и добавляли триэтиламин (8,5 г, 83,7 ммоль). Через 10 минут по каплям добавляли бензоилхлорид (4,7 г, 33,5 ммоль) и раствору давали перемешиваться в течение 60 часов. Осадок затем отфильтровывали и фильтрат концентрировали. Очистка данного продукта методом препаративной ВЭЖХ (хлороформ до 25% этилацетата в градиенте хлороформа) с последующей перекристаллизацией из метанола давала 3,78 г соединения заголовка в виде белого порошка: ¹H-ЯМР (300 МГц, ДМСО-d₆) δ 8,18 (арр т, J = 9,1 Гц, 4H), 7,91-8,05 (сложный, 3H), 7,75 (м, 1H), 7,61-7,69 (м сложный, 2H), 7,58 (д, J = 8,9 Гц, 1H), 7,42-7,50 (сложный, 3H), 7,38 (д, J = 8,3 Гц, 2H), 6,91 (д, J = 8,5 Гц, 2H), 6,80 (д, J = 8,5 Гц, 2H), 4,40 (с, 2H), 3,97 (т, J = 3,5 Гц, 2H), 2,60 (т, J = 3,3 Гц, 2H), 2,39 (сложный, 4H), 1,31-1,52 (сложный, 6H); МС (FD) m/e 661 (M⁺); Анал. расч. для: C 79,86; H 5,94; N 2,12. Найдено: C 79,59; H 6,05; N 1,96.

To a suspension of the product of Example 2 (4.1 g, 8.4 mmol) stirred in THF (200 ml) was added N, N-dimethylaminopyridine (10 mg, as a catalyst). The mixture was cooled to 0 ^° C. and triethylamine (8.5 g, 83.7 mmol) was added. After 10 minutes, benzoyl chloride (4.7 g, 33.5 mmol) was added dropwise and the solution was allowed to stir for 60 hours. The precipitate was then filtered off and the filtrate was concentrated. Purification of this product by preparative HPLC (chloroform to 25% ethyl acetate in a chloroform gradient) followed by recrystallization from methanol gave 3.78 g of the title compound as a white powder: ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.18 (arr t, J = 9.1 Hz, 4H), 7.91-8.05 (complex, 3H), 7.75 (m, 1H), 7.61-7.69 (m complex, 2H), 7.58 (d, J = 8.9 Hz, 1H), 7.42-7.50 (complex, 3H), 7.38 (d, J = 8.3 Hz, 2H), 6.91 (d , J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.40 (s, 2H), 3.97 (t, J = 3.5 Hz, 2H ), 2.60 (t, J = 3.3 Hz, 2H), 2.39 (complex, 4H), 1.31-1.52 (complex, 6H); MS (FD) m / e 661 (M ⁺ ); Anal calc. for: C 79.86; H 5.94; N, 2.12. Found: C, 79.59; H 6.05; N 1.96.

 Example 4

 [2- (4-Pivaloyloxyphenyl) -6-pivaloyloxinaphthalen-1-yl] [4- [2- (2-1-piperidinyl) ethoxy] phenyl] methane.

К суспензии продукта по примеру 2 (0,250 г, 0,510 ммоль), перемешиваемой в ТГФ (25 мл), добавляли N,N-диметиламинопиридин (2 мг) с последующим добавлением триэтиламина (0,78 мл, 5,6 ммоль) и триметилацетилхлорида (0,25 мл, 2,0 ммоль). Полученную смесь перемешивали при температуре окружающей среды в течение 2 часов, затем вливали в этилацетат/воду (100 мл, 1:1 по объему). Органический слой отделяли и водную часть экстрагировали добавлением этилацетата (50 мл). Объединенные органические экстракты промывали насыщенным водным хлоридом аммония (1х25 мл), насыщенным водным бикарбонатом натрия (2х25 мл) и насыщенным раствором соли (1х25 мл). Очистка методом радиальной хроматографии (силикагель, 2 мм, 10:8:1:1 этилацетат:гексаны:триэтиламин: этанол) давала 0,268 г соединения заголовка (85%) в виде густой маслянистой жидкости: ИК (хлороформ) 2977, 2939, 1746, 1510, 1176, 1146, 1122 см^-1; ¹H-ЯМР (300 МГц, CDCl₃) δ 7,87-7,90 (д, 1H, J = 9,3 Гц), 7,75-7,78 (д, 1H, J = 8,6 Гц), 7,56-7,57 (д, 1H, J = 2,4 Гц), 7,43-7,46 (д, 1H, J = 8,4 Гц), 7,28-7,31 (м, 3H), 7,10-7,14 (дд, H1, J = 9,2 Гц, J = 2,4 Гц), 7,03-7,06 (м, 2H), 6,86-6,88 (д, 2Н, J=8,5 Гц), 6,71-6,74 (м, 2H), 4,34 (с, 2H), 4,10-4,15 (м, 2H), 2,79-2,83 (м, 2H), 2,52-2,57 (м, 4H), 1,65-1,68 (м, 4H), 1,45-1,51 (м, 2H), 1,39 (с, 9H), 1,36 (с, 9H); МС (FD) m/e 621 (M⁺).

To a suspension of the product of Example 2 (0.250 g, 0.510 mmol) stirred in THF (25 ml) was added N, N-dimethylaminopyridine (2 mg), followed by triethylamine (0.78 ml, 5.6 mmol) and trimethylacetyl chloride ( 0.25 ml, 2.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hours, then poured into ethyl acetate / water (100 ml, 1: 1 by volume). The organic layer was separated and the aqueous portion was extracted by adding ethyl acetate (50 ml). The combined organic extracts were washed with saturated aqueous ammonium chloride (1x25 ml), saturated aqueous sodium bicarbonate (2x25 ml) and saturated brine (1x25 ml). Purification by radial chromatography (silica gel, 2 mm, 10: 8: 1: 1 ethyl acetate: hexanes: triethylamine: ethanol) afforded 0.268 g of the title compound (85%) as a thick oily liquid: IR (chloroform) 2977, 2939, 1746, 1510, 1176, 1146, 1122 cm ^-1 ; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.87-7.90 (d, 1H, J = 9.3 Hz), 7.75-7.78 (d, 1H, J = 8.6 Hz ), 7.56-7.57 (d, 1H, J = 2.4 Hz), 7.43-7.46 (d, 1H, J = 8.4 Hz), 7.28-7.31 ( m, 3H), 7.10-7.14 (dd, H1, J = 9.2 Hz, J = 2.4 Hz), 7.03-7.06 (m, 2H), 6.86-6 88 (d, 2H, J = 8.5 Hz), 6.71-6.74 (m, 2H), 4.34 (s, 2H), 4.10-4.15 (m, 2H), 2.79-2.83 (m, 2H), 2.52-2.57 (m, 4H), 1.65-1.68 (m, 4H), 1.45-1.51 (m, 2H) ), 1.39 (s, 9H); 1.36 (s, 9H); MS (FD) m / e 621 (M ⁺ ).

 Example 5

 [2- (4-n-Butylsulfonyloxyphenyl) -6-n-butylsulfonyloxy-naphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methane.

К суспензии продукта по примеру 2 (0,250 г, 0,510 ммоль), перемешиваемой в ТГФ (25 мл), добавляли по очереди N,N-диметиламинопиридин (2 мг), триэтиламин (0,78 мл, 5,6 ммоль) и бутансульфонилхлорид (0,26 мл, 2,04 ммоль). Реакционную смесь перемешивали при температуре окружающей среды в течение 2 часов, затем вливали в этилацетат/воду (100 мл, 1:1) и органический слой впоследствии отделяли. Водную часть экстрагировали добавлением этилацетата (50 мл) и объединенные органические слои промывали насыщенным водным хлоридом аммония (1х25 мл), затем насыщенным водным бикарбонатом натрия (2х25 мл) и насыщенным раствором соли (1х25 мл). Очистка методом радиальной хроматографии (силикагель, 2 мм, 10:8:1:1 этилацетат:гексаны:триэтиламин:метанол) давала 0,289 г (82%) соединения заголовка в виде густого сиропа: ИК (хлороформ) 3032, 2966, 2940, 2879, 1609, 1510, 1375, 1245, 1171, 1149, 1129, 870, 839 см^-1; ¹H-ЯМР (300 МГц, CDCl₃) δ 7,92-7,95 (д, 1H, J = 9,3 Гц), 7,81-7,84 (д, 1H, J = 8,6 Гц), 7,77-7,78 (д, 1H, J = 2,5 Гц), 7,46-7,49 (д, 1H, J = 8,4 Гц), 7,24-7,34 (м, 5H), 6,86-6,88 (д, 2H, J = 8,6 Гц), 6,74-6,77 (д, 2H, J = 8,6 Гц), 4,33 (с, 2H), 4,05-4,09 (м, 2H), 3,25-3,32 (м, 4H), 2,72-2,81 (м, 2H), 2,48-2,52 (м, 4H), 1,93-2,06 (м, 4H), 1,44-1,61 (м, 10H), 0,96-1,01 (м, 3H); МС (FD) m/e 694 (M⁺).

To a suspension of the product of Example 2 (0.250 g, 0.510 mmol) stirred in THF (25 ml), N, N-dimethylaminopyridine (2 mg), triethylamine (0.78 ml, 5.6 mmol) and butanesulfonyl chloride ( 0.26 ml, 2.04 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, then poured into ethyl acetate / water (100 ml, 1: 1) and the organic layer was subsequently separated. The aqueous portion was extracted by adding ethyl acetate (50 ml) and the combined organic layers were washed with saturated aqueous ammonium chloride (1x25 ml), then saturated aqueous sodium bicarbonate (2x25 ml) and brine (1x25 ml). Purification by radial chromatography (silica gel, 2 mm, 10: 8: 1: 1 ethyl acetate: hexanes: triethylamine: methanol) afforded 0.289 g (82%) of the title compound as a thick syrup: IR (chloroform) 3032, 2966, 2940, 2879 , 1609, 1510, 1375, 1245, 1171, 1149, 1129, 870, 839 cm ^-1 ; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.92-7.95 (d, 1H, J = 9.3 Hz), 7.81-7.84 (d, 1H, J = 8.6 Hz ), 7.77-7.78 (d, 1H, J = 2.5 Hz), 7.46-7.49 (d, 1H, J = 8.4 Hz), 7.24-7.34 ( m, 5H), 6.86-6.88 (d, 2H, J = 8.6 Hz), 6.74-6.77 (d, 2H, J = 8.6 Hz), 4.33 (s , 2H), 4.05-4.09 (m, 2H), 3.25-3.32 (m, 4H), 2.72-2.81 (m, 2H), 2.48-2.52 (m, 4H), 1.93-2.06 (m, 4H), 1.44-1.61 (m, 10H), 0.96-1.01 (m, 3H); MS (FD) m / e 694 (M ⁺ ).

 Example 6

 [2- (4-n-Hexylsulfonyloxyphenyl) -6-n-hexylsulfonyloxynaphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methane.

К раствору продукта по примеру 2 (0,49 г, 1,00 ммоль), перемешиваемому в ТГФ (200 мл) при температуре окружающей среды, последовательно добавляли N, N-диметилформамид (10 мг), триэтиламин (0,50 г, 5 ммоль) и гексилсульфонилхлорид (0,46 мл, 2,5 ммоль). Через 18 часов реакционную смесь концентрировали и полученную темную маслянистую жидкость делили между этилацетатом и насыщенным водным раствором бикарбоната натрия. Органический экстракт отделяли, сушили (сульфат натрия) и концентрировали. Неочищенный продукт растворяли в этилацетате и добавляли эфирную соляную кислоту (10 мл насыщенного раствора). Полученный осадок растирали с Et₂O и сушили, что давало 1,2 г желательного продукта в виде густого смолистого твердого вещества: ¹H-ЯМР (300 МГц, CDCl₃) согласующийся со структурой; МС (FD) m/e 938 (M⁺-соляная кислота).

To a solution of the product of Example 2 (0.49 g, 1.00 mmol) stirred in THF (200 ml) at ambient temperature, N, N-dimethylformamide (10 mg), triethylamine (0.50 g, 5) were successively added. mmol) and hexylsulfonyl chloride (0.46 ml, 2.5 mmol). After 18 hours, the reaction mixture was concentrated and the resulting dark oily liquid was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic extract was separated, dried (sodium sulfate) and concentrated. The crude product was dissolved in ethyl acetate and ethereal hydrochloric acid (10 ml of saturated solution) was added. The resulting precipitate was triturated with Et ₂ O and dried to give 1.2 g of the desired product as a thick, gummy solid: ¹ H-NMR (300 MHz, CDCl ₃ ) consistent with structure; MS (FD) m / e 938 (M ⁺ hydrochloric acid).

 Getting 4.

 [3,4-Dihydro-2-phenyl-6-methoxynaphthalen-1-yl] (4-hydroxyphenyl) methanone.

К раствору литийэтантиола [полученного путем добавления n-BuLi (63,7 мл 1,6 М раствора в гексане, 101,4 ммоль), к раствору этантиола (101,4 ммоль), перемешиваемому при 0^oC в Et₂O (400 мл), с последующим концентрированием], перемешиваемому в диметилформамиде (400 мл), добавляли (3,4-дигидро-6-метокси-2-фенил-1-нафталинил)(4-метоксифенил)метанон, полученный как описано в Jones, et al., J. Med. Chem., 53:931-938 (1992), выше, (30,0 г, 78,0 ммоль). Смесь затем нагревали до 85^oC. После 0,5 часа смесь концентрировали и полученное коричневое твердое вещество растворяли в хлороформе. Данный раствор экстрагировали добавлением насыщенного водного хлорида аммония. Водную часть обрабатывали 1н. соляной кислотой, пока не получали pH 5, и впоследствии удаляли хлороформ. Объединенные органические экстракты промывали насыщенным раствором соли, сушили (сульфат натрия), фильтровали и концентрировали. Полученную коричневую жидкость очищали методом флэш-хроматографии (силикагель, градиент этилацетата/гексана), что давало 24,7 г (87%) желательного продукта в виде желтой пены: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,74 (д, J = 8,6 Гц, 2H), 7,15-7,18 (м, 2H), 7,05-7,18 (м, 3H), 6,86 (д, J = 8,6 Гц, 1H), 6,78 (д, J = 2,7 Гц, 1H), 6,60-6,70 (м, 3H), 6,23 (ушир. с, 1H), 3,78 (с, 3H), 2,95-3,05 (м, 2H), 2,75-2,85 (м, 2H); Анал. расч. для: C 80,87; H 5,66. Найдено: C 80,66; H 5,48; МС (FD) m/e 354 (M⁺).

To a solution of lithium ethanethiol [prepared by adding n-BuLi (63.7 ml of a 1.6 M solution in hexane, 101.4 mmol), to a solution of ethanethiol (101.4 mmol), stirred at 0 ^° C. in Et ₂ O (400 ml), followed by concentration], stirred in dimethylformamide (400 ml), (3,4-dihydro-6-methoxy-2-phenyl-1-naphthalenyl) (4-methoxyphenyl) methanone obtained as described in Jones, et al., J. Med. Chem., 53: 931-938 (1992), supra, (30.0 g, 78.0 mmol). The mixture was then heated to 85 ^° C. After 0.5 hours, the mixture was concentrated and the resulting brown solid was dissolved in chloroform. This solution was extracted by the addition of saturated aqueous ammonium chloride. The aqueous portion was treated with 1N. hydrochloric acid until a pH of 5 was obtained, and subsequently chloroform was removed. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated. The resulting brown liquid was purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to give 24.7 g (87%) of the desired product as a yellow foam: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.74 ( d, J = 8.6 Hz, 2H), 7.15-7.18 (m, 2H), 7.05-7.18 (m, 3H), 6.86 (d, J = 8.6 Hz , 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.60-6.70 (m, 3H), 6.23 (br s, 1H), 3.78 (s, 3H), 2.95-3.05 (m, 2H), 2.75-2.85 (m, 2H); Anal calc. for: C 80.87; H 5.66. Found: C, 80.66; H 5.48; MS (FD) m / e 354 (M ⁺ ).

 Getting 5.

 [3,4-Dihydro-2-phenyl-6-methoxynaphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methanone.

К раствору продукта по получению 4 (20,4 г, 57,0 ммоль), перемешиваемому в диметилформамиде (400 мл) при температуре окружающей среды, добавляли иодид калия (30 мг, 0,18 ммоль) с последующим добавлением карбоната калия (39,3 г, 285 ммоль) и 1-(2-хлорэтил)пиперидинмоногидрохлорида (11,6 г, 62,7 ммоль). Через 16 часов реакционную смесь концентрировали и полученное масло растворяли в хлороформе. Данный раствор тщательно промывали водой, насыщенным раствором соли, сушили (сульфат натрия), фильтровали и концентрировали. Полученное масло очищали методом флэш-хроматографии (силикагель, градиент метанола/хлороформа), что давало 25,1 г (94%) желательного продукта в виде коричневой маслянистой жидкости: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,79 (д, J = 8,7 Гц, 2H), 7,20-7,33 (м, 2H), 7,04-7,20 (м, 3H), 6,88 (д, J = 8,5 Гц, 1H), 6,70-6,82 (м, 3H), 6,62 (м, 1H), 4,08 (т, J = 6,0 Гц, 2H), 3,70 (с, 3H), 3,03(т, J = 7,5 Гц, 2H), 2,70-2,90 (м, 4H), 2,40-2,60 (м, 4H), 1,55-1,65 (м, 4H), 1,40-1,52 (м, 2H); ¹³C-ЯМР (75 МГц, CDCl₃) δ 198,33, 162,84, 158,97, 141,21, 136,71, 135,97, 137,78, 131,79, 130,44, 128,08, 127,48, 127,24, 126,59, 114,17, 113,80, 111,37, 66,15, 57,68, 55,23, 55,05, 29,73, 28,80, 25,89, 24,12; Анал. Расч. для: C 79,63; H 7,11; N 2,99. Получ: C 79,92; H 7,15; N 3,07. МС (FD) m/e 467 (M⁺).

To a solution of the product of Preparation 4 (20.4 g, 57.0 mmol), stirred in dimethylformamide (400 ml) at ambient temperature, potassium iodide (30 mg, 0.18 mmol) was added followed by potassium carbonate (39, 3 g, 285 mmol) and 1- (2-chloroethyl) piperidine monohydrochloride (11.6 g, 62.7 mmol). After 16 hours, the reaction mixture was concentrated and the resulting oil was dissolved in chloroform. This solution was washed thoroughly with water, brine, dried (sodium sulfate), filtered and concentrated. The resulting oil was purified by flash chromatography (silica gel, methanol / chloroform gradient) to give 25.1 g (94%) of the desired product as a brown oily liquid: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.79 ( d, J = 8.7 Hz, 2H), 7.20-7.33 (m, 2H), 7.04-7.20 (m, 3H), 6.88 (d, J = 8.5 Hz , 1H), 6.70-6.82 (m, 3H), 6.62 (m, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.70 (s, 3H) 3.03 (t, J = 7.5 Hz, 2H), 2.70-2.90 (m, 4H), 2.40-2.60 (m, 4H), 1.55-1.65 (m, 4H), 1.40-1.52 (m, 2H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ 198.33, 162.84, 158.97, 141.21, 136.71, 135.97, 137.78, 131.79, 130.44, 128, 08, 127.48, 127.24, 126.59, 114.17, 113.80, 111.37, 66.15, 57.68, 55.23, 55.05, 29.73, 28.80, 25.89, 24.12; Anal Calc. for: C 79.63; H 7.11; N, 2.99. Receive: C 79.92; H 7.15; N, 3.07. MS (FD) m / e 467 (M ⁺ ).

 Getting 6.

 [3,4-Dihydro-2-phenyl-6-methoxynaphthalen-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] methanone.

Реакция продукта по получению 4 (1,9 г, 5,3 ммоль), 1-(2-хлорэтил)пирролидинмоногидрохлорида (0,99 г, 5,8 ммоль) и карбоната калия (3,65 г, 29,1 ммоль) в диметилформамиде (50 мл) в соответствии с методикой по получению 5 давала 81% выход соединения заголовка в виде густой маслянистой жидкости: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,79 (д, J = 7,8 Гц, 2H), 7,20-7,30 (м, 2H), 7,05-7,20 (м, 3H), 6,87 (д, J = 8,6 Гц, 1H), 6,73-6,84 (м, 3H), 6,60 (д, J = 8,6 Гц, 1H), 4,08 (т, J = 5,8 Гц, 2H), 3,78 (с, 3H), 3,00 (т, J = 8,0 Гц, 2H), 2,76-2,96 (м, 4H), 2,50-2,70 (м, 4H), 1,75-1,85 (м, 4H). МС (FD) m/e 453 (M+).

The reaction of the product to obtain 4 (1.9 g, 5.3 mmol), 1- (2-chloroethyl) pyrrolidine monohydrochloride (0.99 g, 5.8 mmol) and potassium carbonate (3.65 g, 29.1 mmol) in dimethylformamide (50 ml) in accordance with the procedure for obtaining 5 gave 81% yield of the title compound as a thick oily liquid: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.79 (d, J = 7.8 Hz, 2H), 7.20-7.30 (m, 2H), 7.05-7.20 (m, 3H), 6.87 (d, J = 8.6 Hz, 1H), 6.73-6 84 (m, 3H), 6.60 (d, J = 8.6 Hz, 1H), 4.08 (t, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3 00 (t, J = 8.0 Hz, 2H), 2.76-2.96 (m, 4H), 2.50-2.70 (m, 4H), 1.75-1.85 (m , 4H). MS (FD) m / e 453 (M +).

 Example 7

 [3,4-Dihydro-2-phenyl-6-methoxynaphthalen-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] methanol.

К суспензии литийалюминийгидрида (1,60 г, 42,8 ммоль), перемешиваемой при 0^oC в сухом ТГФ (200 мл), добавляли раствор продукта по получению 5 (10,0 г, 21,4 ммоль) в ТГФ (125 мл) по каплям в течение 5-минутного промежутка времени. Реакционной смеси давали нагреться до температуры окружающей среды и впоследствии перемешивали в течение 1 часа. Раствор затем охлаждали до 0^oC и осторожно гасили водой (1,6 мл). К данному раствору по каплям добавляли гидроксид натрия (4,8 мл 15% по массе водного раствора) с последующим добавлением воды (1,6 мл). После перемешивания в течение 30 минут смесь фильтровали и твердые вещества тщательно промывали ТГФ. Фильтрат затем концентрировали, что давало 8,7 г (87% желательного продукта в виде желтого масла, которое использовали без дальнейшей очистки: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,20-7,45 (м, 7H), 6,82 (д, J = 8,3 Гц, 2H), 6,71 (с, 1H), 6,53 (м, 1H), 5,83 (ушир. с, 1H), 4,07 (т, J = 6,1 Гц, 2H), 3,75 (с, 3H), 2,91 (т, J = 6,1 Гц, 2H), 2,60-2,80 (м, 4H), 2,40-2,60 (м, 4H), 1,80-1,95 (м, 2H), 1,52-1,70 (м, 4H), 1,43 (с, 1H); МС (FD) m/e 469 (M+).

To a suspension of lithium aluminum hydride (1.60 g, 42.8 mmol) stirred at 0 ^° C. in dry THF (200 ml) was added a solution of the product to give 5 (10.0 g, 21.4 mmol) in THF (125 ml ) dropwise over a 5 minute period of time. The reaction mixture was allowed to warm to ambient temperature and was subsequently stirred for 1 hour. The solution was then cooled to 0 ^° C. and carefully quenched with water (1.6 ml). Sodium hydroxide (4.8 ml of a 15% by weight aqueous solution) was added dropwise to this solution, followed by the addition of water (1.6 ml). After stirring for 30 minutes, the mixture was filtered and the solids washed thoroughly with THF. The filtrate was then concentrated to give 8.7 g (87% of the desired product as a yellow oil, which was used without further purification: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.20-7.45 (m, 7H) 6.82 (d, J = 8.3 Hz, 2H), 6.71 (s, 1H), 6.53 (m, 1H), 5.83 (br s, 1H), 4.07 ( t, J = 6.1 Hz, 2H), 3.75 (s, 3H), 2.91 (t, J = 6.1 Hz, 2H), 2.60-2.80 (m, 4H), 2.40-2.60 (m, 4H), 1.80-1.95 (m, 2H), 1.52-1.70 (m, 4H), 1.43 (s, 1H); MS ( FD) m / e 469 (M +).

 Example 8

 [3,4-Dihydro-2-phenyl-6-methoxynaphthalen-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] methanol.

Реакция продукта по получению 4 (1,8 г, 4,0 ммоль), литийалюминийгидрида (0,31 г, 8,0 ммоль) в ТГФ (65 мл) в соответствии с получением продукта по примеру 7 давала 87% выход соединения заголовка в виде белой пены: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,20-7,40 (м, 7H), 6,86 (д, J = 8,6 Гц, 2H), 6,71 (с, 1H), 6,51 (м, 1H), 5,83 (д, J = 4,9 Гц, 1H), 4,07 (т, J = 6,3 Гц, 2H), 3,75 (с, 3H), 2,82-2,95 (м, 4H), 2,55-2,73 (м, 6H), 2,27 (д, J = 3,8 Гц, 1H), 1,70-1,90 (м, 4H), 1,67 (с, 1H); MC (FD) m/e 455 (M+); HRMS FAB+ для C₃₀H₃₃NO₃ расчетная 456,2539. Найдено 456,2531.

The reaction of the product to obtain 4 (1.8 g, 4.0 mmol) of lithium aluminum hydride (0.31 g, 8.0 mmol) in THF (65 ml) in accordance with the preparation of the product of Example 7 gave 87% yield of the title compound in as a white foam: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.20-7.40 (m, 7H), 6.86 (d, J = 8.6 Hz, 2H), 6.71 (s , 1H), 6.51 (m, 1H), 5.83 (d, J = 4.9 Hz, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.75 (s , 3H), 2.82-2.95 (m, 4H), 2.55-2.73 (m, 6H), 2.27 (d, J = 3.8 Hz, 1H), 1.70- 1.90 (m, 4H); 1.67 (s, 1H); MS (FD) m / e 455 (M +); HRMS FAB + for C ₃₀ H ₃₃ NO ₃ calculated 456.2539. Found 456.2531.

 Example 9

 [2-Phenyl-6-methoxynaphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methane hydrochloride.

К раствору продукта по примеру 7 (8,7 г, 18,5 ммоль), перемешиваемому в этилацетате (100 мл), добавляли насыщенный раствор хлороводорода в этилацетате (250 мл). Через 0,5 мин полученный раствор концентрировали, что давало 8,0 г (89%) желательного продукта в виде белой пены, которую использовали без дальнейшей очистки: ¹H-ЯМР (300 МГц, ДМСО-d₆) δ 7,70-7,85 (м, 4H), 7,30-7,50 (м, 7H), 7,10 (с, 1H), 6,80-7,00 (м, 2H), 4,25-4,40 (м, 4H), 4,00-4,20 (ушир. с, 3H), 3,35-3,55 (м, 4H), 2,85-3,55 (м, 2H), 1,70-1,90 (м, 4H), 1,30-1,45 (м, 2H); Анал. расч. для: C 76,29; H 7,02; N 2,87. Найдено: C 76,56; H 7,18; N 2,91; МС (FD) m/e 452 (M⁺-соляная кислота).

A saturated solution of hydrogen chloride in ethyl acetate (250 ml) was added to a solution of the product of Example 7 (8.7 g, 18.5 mmol) stirred in ethyl acetate (100 ml). After 0.5 min, the resulting solution was concentrated, which afforded 8.0 g (89%) of the desired product as a white foam, which was used without further purification: ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.70- 7.85 (m, 4H), 7.30-7.50 (m, 7H), 7.10 (s, 1H), 6.80-7.00 (m, 2H), 4.25-4, 40 (m, 4H), 4.00-4.20 (br s, 3H), 3.35-3.55 (m, 4H), 2.85-3.55 (m, 2H), 1, 70-1.90 (m, 4H); 1.30-1.45 (m, 2H); Anal calc. for: C 76.29; H 7.02; N, 2.87. Found: C, 76.56; H 7.18; N, 2.91; MS (FD) m / e 452 (M ⁺ hydrochloric acid).

 Example 10

 [2-Phenyl-6-methoxynaphthalen-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] methane hydrochloride.

Реакция (1,57 г, 3,4 ммоль) с этилацетатом/соляной кислотой в соответствии с методикой примера 9 давала количественный выход указанного в заголовке продукта: ¹H-ЯМР (300 МГц, ДМСО) δ 7,72-7,85 (м, 2H), 7,28-7,45 (м, 7H), 7,10 (м, 1H), 6,78-6,95 (м, 4H), 4,30 (м, 2H), 4,20-4,25 (м, 2H), 3,84 (с, 3H), 3,40-3,60 (м, 2H), 2,95-3,10 (м, 2H), 1,80-2,02 (м, 6H); МС (FD) m/e 437 (M⁺-соляная кислота); Анал. расч. для: C 76,01; H 6,80; N 2,95. Найдено: C 75,71; H 6,85; N 2,82.

The reaction (1.57 g, 3.4 mmol) with ethyl acetate / hydrochloric acid in accordance with the procedure of Example 9 gave a quantitative yield of the title product: ¹ H-NMR (300 MHz, DMSO) δ 7.72-7.85 ( m, 2H), 7.28-7.45 (m, 7H), 7.10 (m, 1H), 6.78-6.95 (m, 4H), 4.30 (m, 2H), 4 , 20-4.25 (m, 2H), 3.84 (s, 3H), 3.40-3.60 (m, 2H), 2.95-3.10 (m, 2H), 1.80 -2.02 (m, 6H); MS (FD) m / e 437 (M ⁺ hydrochloric acid); Anal calc. for: C, 76.01; H 6.80; N, 2.95. Found: C, 75.71; H 6.85; N, 2.82.

 Example 11

 [2-Phenyl-6-hydroxynaphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methane.

К раствору продукта по примеру 9 (4,0 г, 8,0 ммоль), перемешиваемому в 1,2-дихлорэтане (50 мл) при 0^oC, добавляли трихлорид бора (10 мл, 117,0 ммоль). Полученный темно-пурпурный раствор растворяли при комнатной температуре в течение ночи в герметичной пробирке, затем охлаждали при 0^oC. Осторожно по каплям добавляли метанол (50 мл) в течение 30-минутного промежутка времени (осторожно: выделение газа). Полученный раствор концентрировали и растворяли в этилацетате. Органический экстракт промывали насыщенным водным бикарбонатом натрия, насыщенным раствором соли, сушили (сульфат натрия), фильтровали и концентрировали. Полученную коричневую пену очищали методом флэш-хроматографии (силикагель, градиент метанола/хлороформа), что давало 2,7 г (63%) желательного продукта в виде белой пены: ¹H-ЯМР (300 МГц, ДМСО) δ 9,72 (ушир. с, 1H), 7,62-7,80 (м, 2H), 7,22-7,50 (м, 6H), 7,10-7,22 (м, 2H), 7,00 (м, 1H), 6,80-6,90 (м, 2H), 6,78 (м, 1H), 4,23 (с, 2H), 3,85-4,10 (м, 2H), 2,50-2,75 (м, 2H), 2,25-2,50 (м, 4H), 1,25-1,56 (м, 6H); Анал. расч. для: C 82,35; H 7,14; N 3,20. Найдено: C 82,17; H 7,11; N 3,35; МС (FD) m/e 437 (M+); ИК (KBr) 2935,07; 2855,01, 1621,38, 1597,26 см^-1.

Boron trichloride (10 ml, 117.0 mmol) was added to a solution of the product of Example 9 (4.0 g, 8.0 mmol) stirred in 1,2-dichloroethane (50 ml) at 0 ^° C. The resulting dark purple solution was dissolved at room temperature overnight in a sealed tube, then cooled at 0 ^° C. Methanol (50 ml) was carefully added dropwise over a 30 minute period (caution: gas evolution). The resulting solution was concentrated and dissolved in ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate), filtered and concentrated. The resulting brown foam was purified by flash chromatography (silica gel, methanol / chloroform gradient) to give 2.7 g (63%) of the desired product as a white foam: ¹ H-NMR (300 MHz, DMSO) δ 9.72 (broad s, 1H), 7.62-7.80 (m, 2H), 7.22-7.50 (m, 6H), 7.10-7.22 (m, 2H), 7.00 (m , 1H), 6.80-6.90 (m, 2H), 6.78 (m, 1H), 4.23 (s, 2H), 3.85-4.10 (m, 2H), 2, 50-2.75 (m, 2H), 2.25-2.50 (m, 4H), 1.25-1.56 (m, 6H); Anal calc. for: C 82.35; H 7.14; N, 3.20. Found: C, 82.17; H 7.11; N, 3.35; MS (FD) m / e 437 (M +); IR (KBr) 2935.07; 2855.01, 1621.38, 1597.26 cm ^-1 .

 Example 12

 [2-Phenyl-6-hydroxynaphthalen-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] methanol.

Реакция продукта по примеру 10 (1,27 г, 2,7 ммоль) с трихлоридом бора (10 мл, 117 ммоль) в 1,2-дихлорэтане (30 мл) в соответствии с методикой примера 11 давало 32% выход желательного продукта в виде белого твердого вещества: ИК (KBr) 2932,17, 2876,23, 2815,47, 1620,41, 1597,26 см^-1; ¹H-ЯМР (300 МГц, CDCl₃) δ 7,74 (д, J = 8,5 Гц, 1H), 7,61 (д, J = 8,5 Гц, 1H), 7,20-7,40 (м, 7H), 7,13 (с, 1H), 7,00 (м, 1H), 6,85 (д, J = 8,3 Гц, 2H), 6,66 (д, J = 8,3 Гц, 2H), 4,31 (с, 2H), 4,06 (т, J = 5,9 Гц, 2H), 2,95 (т, J = 5,8 Гц, 2H), 2,65-2,80 (м, 4H), 1,77-1,90 (м, 4H); МС (FD) m/e 424 (M+); Анал. расч. для: C 82,24; H 6,90; N 3,31. Найдено: C 82,01; H 6,84; N 3,37.

The reaction of the product of example 10 (1.27 g, 2.7 mmol) with boron trichloride (10 ml, 117 mmol) in 1,2-dichloroethane (30 ml) in accordance with the procedure of example 11 gave 32% yield of the desired product as white solid: IR (KBr) 2932.17, 2876.23, 2815.47, 1620.41, 1597.26 cm ^-1 ; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.74 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.20-7, 40 (m, 7H), 7.13 (s, 1H), 7.00 (m, 1H), 6.85 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 8 , 3 Hz, 2H), 4.31 (s, 2H), 4.06 (t, J = 5.9 Hz, 2H), 2.95 (t, J = 5.8 Hz, 2H), 2, 65-2.80 (m, 4H); 1.77-1.90 (m, 4H); MS (FD) m / e 424 (M +); Anal calc. for: C 82.24; H 6.90; N, 3.31. Found: C, 82.01; H 6.84; N, 3.37.

 Example 13

 [3,4-Dihydro-2- (4-methoxyphenyl) naphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methanol.

К суспензии [2-(4-метоксифенил)-3,4-дигидронафт-1-ил][4-[2-(1- пиперидинил)этокси] фенил] метанонмезилата [Jones, et al., J. Med. Chem. 35:931 (1992), выше] (2,00 г, 3,35 ммоль), перемешиваемой в ТГФ (100 мл) при температуре окружающей среды, медленно добавляли литийалюминийгидрид (1,0 г, 26 ммоль) в течение 20-минутного промежутка времени. Через 18 часов раствор концентрировали почти досуха, затем осторожно гасили водой (50 мл). Полученную смесь экстрагировали добавлением этилацетата (3х100 мл). Объединенные органические экстракты промывали водой, сушили (сульфат натрия) и концентрировали. Очистка методом жидкостной хроматографии (Waters Prep 500, силикагель, градиент от хлороформа до 25% хлороформ:метанол) давала 1,0 г желательного продукта в виде желто-коричневого аморфного порошка: ¹H-ЯМР (300 МГц, CDCl₃) согласующийся со структурой; МС (FD) m/e 469 (M⁺).

To a suspension of [2- (4-methoxyphenyl) -3,4-dihydronaft-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methanone mesylate [Jones, et al., J. Med. Chem. 35: 931 (1992), above] (2.00 g, 3.35 mmol) stirred in THF (100 ml) at ambient temperature, lithium aluminum hydride (1.0 g, 26 mmol) was slowly added over a 20 minute period time lapse. After 18 hours, the solution was concentrated almost to dryness, then carefully quenched with water (50 ml). The resulting mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with water, dried (sodium sulfate) and concentrated. Purification by liquid chromatography (Waters Prep 500, silica gel, gradient from chloroform to 25% chloroform: methanol) gave 1.0 g of the desired product as a tan amorphous powder: ¹ H-NMR (300 MHz, CDCl ₃ ) consistent with structure ; MS (FD) m / e 469 (M ⁺ ).

 Example 14

 [3,4-Dihydro-2- (4-methoxyphenyl) naphthalen-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] methanol.

Реакция [2-(4-метоксифенил)-3,4-дигидронафт-1-ил] [4-[2-(1- пирролидинил)этокси] фенил[метанонмезилата [Jones, et al. , J. Med. Chem. 35:931 (1992), выше] (0,85 г, 1,9 ммоль) и литийалюминийгидрида (0,16 г, 4,0 ммоль) в ТГФ (150 мл) в соответствии с экспериментальной методикой опыта 13 давала желательное соединение в виде желто-коричневого аморфного твердого вещества: ¹H-ЯМР (300 МГц, CDCl₃) согласующийся со структурой; МС (FD) m/e 455 (M⁺); Анал. расч. для: C 79,20; H 7,26; N 3,08. Найдено: C 79,11; H 7,47; N 2,93.

The reaction of [2- (4-methoxyphenyl) -3,4-dihydronaft-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl [methanone mesylate [Jones, et al. , J. Med. Chem. 35: 931 (1992), above] (0.85 g, 1.9 mmol) and lithium aluminum hydride (0.16 g, 4.0 mmol) in THF (150 ml) in accordance with experimental procedure 13 gave the desired compound as a tan amorphous solid: ¹ H-NMR (300 MHz, CDCl ₃ ) consistent with structure; MS (FD) m / e 455 (M ⁺ ); Anal calc. for: C 79.20; H 7.26; N, 3.08. Found: C, 79.11; H 7.47; N, 2.93.

 Example 15

 [2- (4-Methoxyphenyl) naphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methane hydrochloride.

К раствору продукта по примеру 13 (1,90 г, 4,21 ммоль), перемешиваемому в метаноле (40 мл) при температуре окружающей среды, добавляли соляную кислоту в метаноле (10 мл насыщенного раствора). Через 48 часов реакционную смесь концентрировали и сушили. Растирание с эфиром с последующим фильтрованием и сушкой давало 580 мг желательного соединения в виде белого порошка: ¹H-ЯМР (CDCl₃, 300 МГц) согласующийся со структурой; МС (FD) m/e 451 (M⁺-соляная кислота).

To the solution of the product of Example 13 (1.90 g, 4.21 mmol) stirred in methanol (40 ml) at ambient temperature was added hydrochloric acid in methanol (10 ml of a saturated solution). After 48 hours, the reaction mixture was concentrated and dried. Trituration with ether, followed by filtration and drying gave 580 mg of the desired compound as a white powder: ¹ H-NMR (CDCl ₃ , 300 MHz) consistent with structure; MS (FD) m / e 451 (M ⁺ hydrochloric acid).

 Example 16

 [2- (4-Methoxyphenyl) naphthalen-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] methane hydrochloride.

К раствору продукта по примеру 14 (2,0 г, 4,58 ммоль), перемешиваемому в метаноле (50 мл) при температуре окружающей среды, добавляли соляную кислоту в метаноле (10 мл насыщенного раствора). Реакционную смесь затем концентрировали до 20 мл и охлаждали до -20^oC в течение нескольких часов. Фильтрование давало 0,62 г желательного продукта в виде белого порошка: ¹H-ЯМР (CDCl₃, 300 МГц) согласующийся со структурой; МС (FD) m/e 437 (M⁺-соляная кислота); Анал. расч. для: C 76,01; H 6,80; N 2,96. Получ: C 75,95; H 6,76; N 2,98.

To a solution of the product of Example 14 (2.0 g, 4.58 mmol) stirred in methanol (50 ml) at ambient temperature was added hydrochloric acid in methanol (10 ml of a saturated solution). The reaction mixture was then concentrated to 20 ml and cooled to -20 ^o C for several hours. Filtration gave 0.62 g of the desired product as a white powder: ¹ H-NMR (CDCl ₃ , 300 MHz) consistent with structure; MS (FD) m / e 437 (M ⁺ hydrochloric acid); Anal calc. for: C, 76.01; H 6.80; N, 2.96. Receive: C 75.95; H 6.76; N, 2.98.

 Getting 7.

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] methanone.

К раствору по получению 2 (2,0 г, 5,2 ммоль), перемешиваемому в диметилформамиде (50 мл), добавляли карбонат калия (3,6 г, 26 ммоль) и 1-(2-хлорэтил)пирролидин-моногидрохлорид (0,8 г, 5,7 ммоль). Реакционную смесь перемешивали в течение ночи при температуре окружающей среды и концентрировали. Полученное масло растворяли в хлороформе и полученный раствор тщательно промывали водой, насыщенным раствором соли, сушили (сульфат натрия), фильтровали и концентрировали. Полученное масло очищали методом флэш-хроматографии (силикагель, градиент метанола/хлороформа), что давало 2,25 г (90%) желательного продукта в виде коричневой маслянистой жидкости: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,80 (д, J = 9,4 Гц, 2H), 7,18 (д, J = 6,8 Гц, 2H), 6,87 (д, J = 8,6 Гц, 2H), 6,65-6,85 (м, 4H), 6,60 (м, 1H), 4,09 (т, J = 5,8 Гц, 2H), 3,78 (с, 3H), 3,71 (с, 3H), 3,01 (т, J = 7,5 Гц, 2H), 2,88 (т, J = 5,8 Гц, 2H), 2,65-2,85 (м, 2H), 2,60-2,75 (м, 4H), 1,80-1,90 (м, 4H); МС (FD) m/e 483 (M+).

To a solution of Preparation 2 (2.0 g, 5.2 mmol) stirred in dimethylformamide (50 ml) was added potassium carbonate (3.6 g, 26 mmol) and 1- (2-chloroethyl) pyrrolidine monohydrochloride (0 8 g, 5.7 mmol). The reaction mixture was stirred overnight at ambient temperature and concentrated. The resulting oil was dissolved in chloroform, and the resulting solution was thoroughly washed with water, brine, dried (sodium sulfate), filtered and concentrated. The resulting oil was purified by flash chromatography (silica gel, methanol / chloroform gradient) to give 2.25 g (90%) of the desired product as a brown oily liquid: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.80 ( d, J = 9.4 Hz, 2H), 7.18 (d, J = 6.8 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.65-6, 85 (m, 4H), 6.60 (m, 1H), 4.09 (t, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 3.01 (t, J = 7.5 Hz, 2H), 2.88 (t, J = 5.8 Hz, 2H), 2.65-2.85 (m, 2H), 2.60-2 75 (m, 4H); 1.80-1.90 (m, 4H); MS (FD) m / e 483 (M +).

 Example 17

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] methanol.

К суспензии литийалюминийгидрида (0,34 г, 8,80 ммоль), перемешиваемой при 80^oC в ТГФ (40 мл), медленно добавляли раствор продукта по получению 7 (2,14 г, 4,4 ммоль) в ТГФ (25 мл) в течение 5-минутного промежутка времени. Реакционную смесь нагревали до температуры окружающей среды. Через 1 час смесь охлаждали до 0^oC и осторожно гасили водой (0,4 мл). К данному раствору по каплям добавляли гидроксид натрия (1,2 мл 15% по массе водного раствора) с последующим добавлением воды (0,4 мл). После перемешивания в течение 30 минут смесь фильтровали и твердые вещества тщательно промывали ТГФ. Фильтрат концентрировали, что давало 1,60 г (75%) желательного продукта в виде белой пены, которую использовали без дальнейшей очистки: ¹H-ЯМР (300 МГц, ДМСО) δ 7,40 (д, J = 8,2 Гц, 2H), 7,33 (д, J = 7,6 Гц, 1H), 7,16 (д, J = 8,1 Гц, 2H), 6,90 (д, J = 7,7 Гц, 2H), 6,75 (д, J = 7,8 Гц, 2H), 6,66 (с, 1H), 6,45 (д, J = 7,6 Гц, 1H), 5,69 (с, 1H), 5,64 (с, 1H), 3,95 (т, J = 5,5 Гц, 2H), 3,72 (с, 3H), 3,64 (с, 3H), 2,65-2,85 (м, 4H), 2,40-2,65 (м, 6H), 1,60-1,80 (м, 4H); МС (FD) m/e 485 (M+).

To a suspension of lithium aluminum hydride (0.34 g, 8.80 mmol) stirred at 80 ^° C. in THF (40 ml) was slowly added a solution of the product to obtain 7 (2.14 g, 4.4 mmol) in THF (25 ml ) for a 5 minute period of time. The reaction mixture was heated to ambient temperature. After 1 hour, the mixture was cooled to 0 ^° C. and carefully quenched with water (0.4 ml). Sodium hydroxide (1.2 ml of a 15% by weight aqueous solution) was added dropwise to this solution, followed by the addition of water (0.4 ml). After stirring for 30 minutes, the mixture was filtered and the solids washed thoroughly with THF. The filtrate was concentrated to give 1.60 g (75%) of the desired product as a white foam, which was used without further purification: ¹ H-NMR (300 MHz, DMSO) δ 7.40 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 7.7 Hz, 2H) 6.75 (d, J = 7.8 Hz, 2H), 6.66 (s, 1H), 6.45 (d, J = 7.6 Hz, 1H), 5.69 (s, 1H) 5.64 (s, 1H), 3.95 (t, J = 5.5 Hz, 2H), 3.72 (s, 3H), 3.64 (s, 3H), 2.65-2, 85 (m, 4H), 2.40-2.65 (m, 6H), 1.60-1.80 (m, 4H); MS (FD) m / e 485 (M +).

 Example 18

 [2- (4-Methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] methane hydrochloride.

К раствору продукта по примеру 17 (1,61 г, 3,30 ммоль), перемешиваемому в этилацетате (50 мл) при температуре окружающей среды, добавляли насыщенный раствор хлороводорода в этилацетате (50 мл). Полученную смесь концентрировали, что давало 1,66 г (100%) желательного продукта в виде белой пены, которую использовали без дальнейшей очистки: ¹H-ЯМР (300 МГц, ДМСО-d₆) δ 7,70-7,80 (м, 2H), 7,30-7,40 (м, 2H), 7,20-7,30 (м, 2H), 7,05 (м, 1H), 6,80-7,00 (м, 6H), 4,29 (с, 2H), 4,20-4,25 (м, 2H), 3,84 (с, 3H), 3,75 (с, 3H), 3,42-3,75 (м, 4H), 3,00-3,15 (м, 2H), 1,80-2,00 (м, 4H); МС (FD) m/e 467 (M⁺-соляная кислота).

To a solution of the product of Example 17 (1.61 g, 3.30 mmol) stirred in ethyl acetate (50 ml) at ambient temperature was added a saturated solution of hydrogen chloride in ethyl acetate (50 ml). The resulting mixture was concentrated to give 1.66 g (100%) of the desired product as a white foam, which was used without further purification: ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.70-7.80 (m , 2H), 7.30-7.40 (m, 2H), 7.20-7.30 (m, 2H), 7.05 (m, 1H), 6.80-7.00 (m, 6H ), 4.29 (s, 2H), 4.20-4.25 (m, 2H), 3.84 (s, 3H), 3.75 (s, 3H), 3.42-3.75 ( m, 4H), 3.00-3.15 (m, 2H), 1.80-2.00 (m, 4H); MS (FD) m / e 467 (M ⁺ hydrochloric acid).

 Example 19

 [2- (4-Hydroxyphenyl) -6-hydroxy-naphthalen-1-yl] [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] methane.

К раствору продукта по примеру 18 (1,61 г, 2,60 ммоль) в 1,2-дихлорэтане (30 мл), перемешивая при 0^oC, добавляли трихлорид бора (10 мл, 117 ммоль). Полученный темно-пурпурный раствор перемешивали в течение ночи при температуре окружающей в герметичной пробирке. После охлаждения раствора до 0^oC осторожно добавляли метанол (25 мл) в течение 30-минутного промежутка времени (осторожно, выделение газа). Раствор впоследствии концентрировали и полученный продукт растворяли в 30% изопропаноле/хлороформе, затем промывали насыщенным бикарбонатом натрия, насыщенным раствором соли, сушили над безводным сульфатом натрия, фильтровали и концентрировали. Неочищенный продукт очищали методом радиальной хроматографии (градиент метанола/хлороформа), что давало 0,34 г (27%) желательного продукта в виде белой пены: ¹H-ЯМР (300 МГц, ДМСО-d₆) δ 9,45 (с, 1H), 9,36 (с, 1H), 7,72 (д, J = 8,8 Гц, 1H), 7,62 (д, J = 9,2 Гц, 1H), 7,28 (д, J = 8,7 Гц, 1H), 7,00-7,10 (м, 2H), 6,80-6,90 (м, 2H), 6,70-6,80 (м, 4H), 5,45 (с, 1H), 4,84 (с, 1H), 4,25 (с, 2H), 3,90-4,05 (м, 2H), 2,75-2,90 (м, 2H), 2,50-2,65 (м, 4H), 1,60-1,80 (м, 4H); ¹³C-ЯМР (75 МГц, ДМСО-d₆) δ 203,32, 191,97, 188,16, 186,14, 185,95, 177,43, 173,46, 169,60, 167,74, 163,48, 162,30, 159,87, 158,14, 154,98, 152,43, 60,50, 56,25, 54,00, 45,05, 41,00, 37,50, 35,00, 30,05, 27,50, 26,00, 22,50, 20,00; Анал. расч. для: C 79,24; H 6,65; N 3,19. Получ: C 78,99; H 6,51; N 2,92. МС (FD) m/e 440 (M+); ИК (KBr) 3382,61, 2964,00, 1610,77, 1509,49 см^-1.

To a solution of the product of Example 18 (1.61 g, 2.60 mmol) in 1,2-dichloroethane (30 ml), boron trichloride (10 ml, 117 mmol) was added while stirring at 0 ^° C. The resulting dark purple solution was stirred overnight at ambient temperature in a sealed tube. After cooling the solution to 0 ^° C., methanol (25 ml) was carefully added over a 30-minute period of time (carefully, gas evolution). The solution was subsequently concentrated and the resulting product was dissolved in 30% isopropanol / chloroform, then washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by radial chromatography (methanol / chloroform gradient), which afforded 0.34 g (27%) of the desired product as a white foam: ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 9.36 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.00-7.10 (m, 2H), 6.80-6.90 (m, 2H), 6.70-6.80 (m, 4H), 5 45 (s, 1H), 4.84 (s, 1H), 4.25 (s, 2H), 3.90-4.05 (m, 2H), 2.75-2.90 (m, 2H) ), 2.50-2.65 (m, 4H); 1.60-1.80 (m, 4H); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) δ 203.32, 191.97, 188.16, 186.14, 185.95, 177.43, 173.46, 169.60, 167.74, 163.48, 162.30, 159.87, 158.14, 154.98, 152.43, 60.50, 56.25, 54.00, 45.05, 41.00, 37.50, 35, 00, 30.05, 27.50, 26.00, 22.50, 20.00; Anal calc. for: C 79.24; H 6.65; N, 3.19. Receive: C 78.99; H 6.51; N, 2.92. MS (FD) m / e 440 (M +); IR (KBr) 3382.61, 2964.00, 1610.77, 1509.49 cm ^-1 .

 Getting 8.

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-N, N-dimethylamino) ethoxy] phenyl] methanone.

Реакция продукта по получению 2 (1,6 г, 4,1 ммоль) 2-диэтиламиноэтилхлоридгидрохлорида (0,8 г, 4,5 ммоль) и карбоната калия (2,3 г, 16,4 ммоль) в диэтилформамиде (50 мл) в соответствии с методикой по получению 3 давала 95% выход желательного продукта: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,82 (д, J=8,8 Гц, 2Н), 7,20 (д, J = 8,7 Гц, 2H), 6,89 (д, J = 8,5 Гц, 1H), 6,65-6,80 (м, 5H), 6,62 (м, 1H), 4,03 (т, J = 6,3 Гц, 2H), 3,80 (с, 3H), 3,72 (с, 3H), 3,03 (т, J = 7,7 Гц, 2H), 2,75-2,90 (м, 4H), 2,61 (ABк, J = 7,2 Гц, Δν = 14,4 Гц, 4H), 1,06 (т, J = 7,2 Гц, 6H); МС (FD) m/e 485 (M+); Анал. расч. для: C 76,67; H 7,26; N 2,88. Получ: C 76,97; H 7,43; N 2,91.

The reaction of the product to obtain 2 (1.6 g, 4.1 mmol) of 2-diethylaminoethyl chloride hydrochloride (0.8 g, 4.5 mmol) and potassium carbonate (2.3 g, 16.4 mmol) in diethylformamide (50 ml) in accordance with the procedure for obtaining 3 gave 95% yield of the desired product: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.82 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.5 Hz, 1H), 6.65-6.80 (m, 5H), 6.62 (m, 1H), 4.03 ( t, J = 6.3 Hz, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 3.03 (t, J = 7.7 Hz, 2H), 2.75- 2.90 (m, 4H), 2.61 (ABc, J = 7.2 Hz, Δν = 14.4 Hz, 4H), 1.06 (t, J = 7.2 Hz, 6H); MS (FD) m / e 485 (M +); Anal calc. for: C 76.67; H 7.26; N, 2.88. Receive: C 76.97; H 7.43; N, 2.91.

 Getting 9.

 [3,4-Dihydro-2- (4-methoxyphenyl) -2,4-dihydro-6-methoxynaphthalen-1-yl] [4- [3- (1-piperidinyl) propoxy] phenyl] methanone.

Реакция продукта по получению 2 (1,6 г, 4,1 ммоль), 1-(3-хлорпропил)пиперидингидрохлорида (0,9 г, 4,5 ммоль) и карбоната калия (2,3 г, 16,4 ммоль) в ДМФ (50 мл) в соответствии с методикой по получению 7 давала 95% выход желательного продукта: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,80 (д, J = 8,7 Гц, 2H), 7,19 (д, J = 5,0 Гц, 2H), 6,86 (д, J = 8,4 Гц, 1H), 6,63-6,80 (м, 5H), 6,60 (м, 1H), 3,98 (т, J = 6,4 Гц, 2H), 3,78 (с, 3H), 3,70 (с, 3H), 3,00 (т, J = 7,7 Гц, 2H), 2,75-2,85 (м, 2H), 2,30-2,50 (м, 6H), 1,90-2,00 (м, 2H), 1,50-1,65 (м, 4H), 1,40-1,50 (м, 2H); МС (FD) m/e 511 (M+); Анал. расч. для: C 77,47; H 7,29; N 2,74. Получ: C 77,42; H 7,36; N 2,72.

The reaction of the product to obtain 2 (1.6 g, 4.1 mmol), 1- (3-chloropropyl) piperidine hydrochloride (0.9 g, 4.5 mmol) and potassium carbonate (2.3 g, 16.4 mmol) in DMF (50 ml) in accordance with the procedure for obtaining 7 gave 95% yield of the desired product: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.7 Hz, 2H), 7, 19 (d, J = 5.0 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.63-6.80 (m, 5H), 6.60 (m, 1H ), 3.98 (t, J = 6.4 Hz, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 3.00 (t, J = 7.7 Hz, 2H ), 2.75-2.85 (m, 2H), 2.30-2.50 (m, 6H), 1.90-2.00 (m, 2H), 1.50-1.65 (m 4H), 1.40-1.50 (m, 2H); MS (FD) m / e 511 (M +); Anal calc. for: C 77.47; H 7.29; N 2.74. Receive: C 77.42; H 7.36; N 2.72.

 Example 20

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-N, N-diethylamino) ethoxy] phenyl] methanol.

Реакция продукта по получению 8 (1,7 г, 3,4 ммоль) с литийалюминийгидридом (0,3 г, 6,8 ммоль) в ТГФ (80 мл) в соответствии с методикой примера 17 давала количественный выход желательного продукта: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,33 (д, J = 8,5 Гц, 2H), 7,20-7,30 (м, 3H), 6,80-6,90 (м, 4H), 6,71 (с, 1H), 6,50 (м, 1H), 5,85 (д, J = 3,9 Гц, 1H), 4,01 (т, J = 6,4 Гц, 2H), 3,78 (с, 3H), 3,74 (с, 3H), 2,86 (ABк, J = 8,2 Гц, Δν = 14,7 Гц, 4H), 2,60-2,70 (м, 6H), 1,85 (м, 1H), 1,05 (т, J = 7,2 Гц, 6H); МС (FD) m/e 487 (M+).

The reaction of the product to obtain 8 (1.7 g, 3.4 mmol) with lithium aluminum hydride (0.3 g, 6.8 mmol) in THF (80 ml) in accordance with the procedure of example 17 gave a quantitative yield of the desired product: ¹ H- NMR (300 MHz, CDCl ₃ ) δ 7.33 (d, J = 8.5 Hz, 2H), 7.20-7.30 (m, 3H), 6.80-6.90 (m, 4H) , 6.71 (s, 1H), 6.50 (m, 1H), 5.85 (d, J = 3.9 Hz, 1H), 4.01 (t, J = 6.4 Hz, 2H) , 3.78 (s, 3H), 3.74 (s, 3H), 2.86 (ABk, J = 8.2 Hz, Δν = 14.7 Hz, 4H), 2.60-2.70 ( m, 6H), 1.85 (m, 1H), 1.05 (t, J = 7.2 Hz, 6H); MS (FD) m / e 487 (M +).

 Example 21

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [3- (1-piperidinyl) propoxy] phenyl] methanol.

Реакция продукта по получению 9 (1,77 г, 3,50 ммоль) с литийалюминийгидридом (0,27 г, 7,00 ммоль) в ТГФ (50 мл) в соответствии с методикой по примеру 17 давала 97% выход желательного продукта: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,32 (д, J = 8,4 Гц, 2H), 7,20-7,30 (м, 4H), 6,80-6,90 (м, 3H), 6,70 (с, 1H), 6,50 (м, 1H), 5,85 (с, 1H), 3,96 (т, J = 6,3 Гц, 2H), 3,78 (с, 3H), 3,74(с, 3H), 2,85-2,95 (м, 2H), 2,60-2,70 (м, 2H), 2,25-2,50 (м, 6H), 1,90-2,00 (м, 2H), 1,54-1,60 (м, 4H), 1,43 (с, 2H); МС (FD) m/e 514 (M⁺¹).

The reaction of the product to obtain 9 (1.77 g, 3.50 mmol) with lithium aluminum hydride (0.27 g, 7.00 mmol) in THF (50 ml) in accordance with the method of example 17 gave 97% yield of the desired product: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.32 (d, J = 8.4 Hz, 2H), 7.20-7.30 (m, 4H), 6.80-6.90 (m, 3H), 6.70 (s, 1H), 6.50 (m, 1H), 5.85 (s, 1H), 3.96 (t, J = 6.3 Hz, 2H), 3.78 ( s, 3H), 3.74 (s, 3H), 2.85-2.95 (m, 2H), 2.60-2.70 (m, 2H), 2.25-2.50 (m, 6H), 1.90-2.00 (m, 2H), 1.54-1.60 (m, 4H), 1.43 (s, 2H); MS (FD) m / e 514 (M ⁺¹ ).

 Example 22

 [2- (4-Methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-N, N-diethylamino) ethoxy] phenyl] methane hydrochloride.

Реакция продукта по примеру 20 (1,6 г, 3,3 ммоль) с соляной кислотой (100 мл насыщенного раствора в этилацетате) в этилацетате (100 мл) в соответствии с методикой по примеру 18 давала 90% выход желательного продукта: ИК (KBr) 3416,37, 2935,07, 2835,72, 2575,30, 2437,37, 1624,27, 1608,84, 1510,45 см^-1; ¹H-ЯМР (300 МГц, CDCl₃) δ 7,72 (т, J = 8,6 Гц, 2H), 7,15-7,30 (м, 4H), 7,05 (м, 1H), 6,85-6,95 (м, 3H), 6,72 (д, J = 8,6 Гц, 2H), 4,40-4,50 (м, 2H), 4,35 (с, 3H), 3,92 (с, 3H), 3,83 (с, 3H), 3,35-3,45 (м, 2H), 3,20-3,35 (м, 4H), 1,43 (т, J = 7,2 Гц, 6H); МС (FD) m/e 470 (M+ -соляная кислота); Анал. расч. для: C 73,57; H 7,17; N 2,77. Найдено: C 73,80; H 7,35; N 2,77.

The reaction of the product of example 20 (1.6 g, 3.3 mmol) with hydrochloric acid (100 ml of a saturated solution in ethyl acetate) in ethyl acetate (100 ml) in accordance with the procedure of example 18 gave 90% yield of the desired product: IR (KBr ) 3416.37, 2935.07, 2835.72, 2575.30, 2437.37, 1624.27, 1608.84, 1510.45 cm ^-1 ; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.72 (t, J = 8.6 Hz, 2H), 7.15-7.30 (m, 4H), 7.05 (m, 1H), 6.85-6.95 (m, 3H), 6.72 (d, J = 8.6 Hz, 2H), 4.40-4.50 (m, 2H), 4.35 (s, 3H) 3.92 (s, 3H), 3.83 (s, 3H), 3.35-3.45 (m, 2H), 3.20-3.35 (m, 4H), 1.43 (t , J = 7.2 Hz, 6H); MS (FD) m / e 470 (M + hydrochloric acid); Anal calc. for: C 73.57; H 7.17; N, 2.77. Found: C, 73.80; H 7.35; N, 2.77.

 Example 23

 [2- (4-Methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [3- (1-piperidinyl) propoxy] phenyl] methane hydrochloride.

Реакция продукта по примеру 21 (1,5 г, 2,9 ммоль) с соляной кислотой (50 мл насыщенного этилацетатного раствора) в этилацетате (50 мл) в соответствии с методикой по примеру 18 давала 97% выход желательного продукта: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,70-7,80 (м, 2H), 7,42 (д, J = 8,4 Гц, 1H), 7,15-7,30 (м, 3H), 7,05 (м, 1H), 6,85-6,95 (м, 4H), 6,69 (д, J = 8,6 Гц, 2H), 4,34 (с, 2H), 3,97-4,03 (м, 2H), 3,92 (с, 3H), 3,82 (с, 3H), 3,50-3,60 (м, 2H), 2,57-2,70 (м, 2H), 2,20-2,50 (м, 4H), 1,80-2,00 (м, 4H); МС (FD) m/e 495 (M+ - соляная кислота); Анал. расч. для: C 74,49; H 7,20; N 2,63. найдено: C 74,74; H 7,36; N 2,75.

The reaction of the product of example 21 (1.5 g, 2.9 mmol) with hydrochloric acid (50 ml of a saturated ethyl acetate solution) in ethyl acetate (50 ml) in accordance with the procedure of example 18 gave a 97% yield of the desired product: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.70-7.80 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.15-7.30 (m, 3H), 7.05 (m, 1H), 6.85-6.95 (m, 4H), 6.69 (d, J = 8.6 Hz, 2H), 4.34 (s, 2H), 3.97 -4.03 (m, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.50-3.60 (m, 2H), 2.57-2.70 (m , 2H); 2.20-2.50 (m, 4H); 1.80-2.00 (m, 4H); MS (FD) m / e 495 (M + - hydrochloric acid); Anal calc. for: C 74.49; H 7.20; N, 2.63. Found: C, 74.74; H 7.36; N, 2.75.

 Example 24

 [2- (4-Hydroxyphenyl) -6-hydroxy-naphthalen-1-yl] [4- [2- (1-N, N-diethylamino) ethoxy] phenyl] methane.

Реакция продукта по примеру 22 (1,32 г, 2,60 ммоль) с трихлоридом бора (10,0 мл, 117,0 ммоль) в 1,2-дихлорэтане (30 мл) в соответствии с методикой по примеру 19 давала 76% выход желательного продукта в виде белого порошка: ИК (KBr) 3356,57, 2973,65, 1734,23, 1704,33, 1610,77, 1509,49 см^-1; ¹H-ЯМР (300 МГц, ДМСО-d₆) δ 9,62 (с, 1H), 9,43 (с, 1H), 7,56-7,70 (м, 2H), 7,24 (д, J = 8,4 Гц, 1H), 7,00-7,15 (м, 3H), 6,95 (м, 1H), 6,82 (д, J = 8,6 Гц, 2H), 6,65-6,78 (м, 4H), 4,23 (с, 2H), 4,00 (т, J = 6,4 Гц, 2H), 2,65-2,75 (м, 2H), 2,40-2,60 (м, 4H), 0,90 (т, J = 7,1 Гц, 6H); ¹³C-ЯМР (75 МГц, ДМСО-d₆) δ 156,53, 156,45, 154,87, 136,65, 134,44, 133,49, 132,66, 132,28, 130,14, 128,90, 128,73, 126,93, 126,57, 125,18, 118,73, 115,01, 114,32, 109,43, 66,22, 51,43, 47,00, 39,00, 33,81, 11,87; МС (FD) m/e 442 (M+); HRMS (FАB+) для C₂₉H₃₁NO₃ рассчитано 442,2382, получено 442,2381.

The reaction of the product of example 22 (1.32 g, 2.60 mmol) with boron trichloride (10.0 ml, 117.0 mmol) in 1,2-dichloroethane (30 ml) in accordance with the procedure of example 19 gave 76% the yield of the desired product in the form of a white powder: IR (KBr) 3356.57, 2973.65, 1734.23, 1704.33, 1610.77, 1509.49 cm ^-1 ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.62 (s, 1H), 9.43 (s, 1H), 7.56-7.70 (m, 2H), 7.24 (d , J = 8.4 Hz, 1H), 7.00-7.15 (m, 3H), 6.95 (m, 1H), 6.82 (d, J = 8.6 Hz, 2H), 6 65-6.78 (m, 4H), 4.23 (s, 2H), 4.00 (t, J = 6.4 Hz, 2H), 2.65-2.75 (m, 2H), 2.40-2.60 (m, 4H); 0.90 (t, J = 7.1 Hz, 6H); ¹³ C-NMR (75 MHz, DMSO-d ₆ ) δ 156.53, 156.45, 154.87, 136.65, 134.44, 133.49, 132.66, 132.28, 130.14, 128.90, 128.73, 126.93, 126.57, 125.18, 118.73, 115.01, 114.32, 109.43, 66.22, 51.43, 47.00, 39, 00, 33.81, 11.87; MS (FD) m / e 442 (M +); HRMS (FAB +) for C ₂₉ H ₃₁ NO ₃ calculated 442.2382, obtained 442.2381.

 Getting 10.

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [3- (1-bromo) ethoxy] phenyl] methanone.

К раствору продукта по получению 2 (4,00 г, 10,0 ммоль), перемешиваемому в 2-бутаноле (100 мл) при температуре окружающей среды, добавляли карбонат калия (2,76 г, 20,0 ммоль) и 1,2-дибромэтан (17,2 мл, 100 ммоль). Данный раствор нагревали с обратным холодильником в течение ночи, затем фильтровали и концентрировали. Полученное коричневое масло очищали методом флэш-хроматографии (силикагель, 20% этилацетат/гексаны), что давало 4,40 г (89%) желательного продукта в виде коричневой маслянистой жидкости. ¹H-ЯМР (300 МГц, CDCl₃) δ 7,81 (д, J = 8,7 Гц, 2H), 7,18 (д, J = 8,7 Гц, 2H), 6,86 (д, J = 8,6 Гц, 1H), 6,76 (д, J = 6,1 Гц, 3H), 6,78 (д, J = 6,8 Гц, 2H), 6,60 (м, 1H), 4,26 (т, J = 6,1 Гц, 2H), 3,78 (с, 3H), 3,70 (с, 3H), 3,60 (т, J = 6,4 Гц, 2H), 3,01 (т, J = 7,7 Гц, 2H), 2,75-2,85 (м, 2H); Анал. расч. для: C 65,73; H 5,11. Найдено: C 65,96; H 5,28.

To a solution of the product to obtain 2 (4.00 g, 10.0 mmol), stirred in 2-butanol (100 ml) at ambient temperature, was added potassium carbonate (2.76 g, 20.0 mmol) and 1.2 dibromoethane (17.2 ml, 100 mmol). This solution was refluxed overnight, then filtered and concentrated. The resulting brown oil was purified by flash chromatography (silica gel, 20% ethyl acetate / hexanes) to give 4.40 g (89%) of the desired product as a brown oily liquid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.81 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.6 Hz, 1H), 6.76 (d, J = 6.1 Hz, 3H), 6.78 (d, J = 6.8 Hz, 2H), 6.60 (m, 1H) 4.26 (t, J = 6.1 Hz, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 3.60 (t, J = 6.4 Hz, 2H) 3.01 (t, J = 7.7 Hz, 2H); 2.75-2.85 (m, 2H); Anal calc. for: C 65.73; H 5.11. Found: C, 65.96; H 5.28.

 Getting 11.

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [3- (1-hexamethyleneiminyl) ethoxy] phenyl] methanone.

К продукту по получению 10 (2,1 г, 4,3 ммоль), перемешиваемому в диметилформамиде (50 мл) при температуре окружающей среды, добавляли карбонат калия (1,8 г, 13 ммоль) и гексаметиленимин (0,9 мл, 13 ммоль). Раствор впоследствии нагревали до 100^oC. После перемешивания в течение ночи смесь концентрировали и полученное коричневое масло делили между хлороформом и водой. Органический экстракт промывали насыщенным раствором соли, сушили (сульфат натрия), фильтровали и концентрировали. Полученную желтую маслянистую жидкость очищали методом радиальной хроматографии (градиент этилацетата/гексана/метанола), что давало 0,95 г (43%) желательного продукта в виде желтого масла: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,81 (д, J = 8,7 Гц, 2H), 7,21 (д, J = 6,9 Гц, 1H), 6,81 (д, J = 8,5 Гц, 1H), 6,60-6,85 (м, 7H), 4,00-4,50 (м, 2H), 3,80 (с, 3H), 3,72 (с, 3H), 2,85-3,10 (м, 4H), 2,70-2,85 (м, 6H), 1,50-1,80 (м, 8H); Анал. расч. для: C 77,47; H 7,29; N 2,74. найдено: C 77,25; H 7,16; N 2,71; МС (FD) m/e 511 (M+).

Potassium carbonate (1.8 g, 13 mmol) and hexamethyleneimine (0.9 ml, 13) were added to the product of Preparation 10 (2.1 g, 4.3 mmol) stirred in dimethylformamide (50 ml) at ambient temperature. mmol). The solution was subsequently heated to 100 ^° C. After stirring overnight, the mixture was concentrated and the resulting brown oil was partitioned between chloroform and water. The organic extract was washed with brine, dried (sodium sulfate), filtered and concentrated. The resulting yellow oily liquid was purified by radial chromatography (gradient of ethyl acetate / hexane / methanol) to give 0.95 g (43%) of the desired product as a yellow oil: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.81 ( d, J = 8.7 Hz, 2H), 7.21 (d, J = 6.9 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.60-6, 85 (m, 7H), 4.00-4.50 (m, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 2.85-3.10 (m, 4H) 2.70-2.85 (m, 6H); 1.50-1.80 (m, 8H); Anal calc. for: C 77.47; H 7.29; N 2.74. Found: C, 77.25; H 7.16; N 2.71; MS (FD) m / e 511 (M +).

 Example 25

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-hexamethyleneiminyl) ethoxy] phenyl] methanol.

К суспензии литийалюминийгидрида (0,3 г, 7,2 ммоль), перемешиваемой при 0^oC в ТГФ (40 мл), медленно добавляли раствор продукта по получению 11 (1,8 г, 3,6 ммоль) в ТГФ (25 мл) в течение 5-минутного промежутка времени. Реакционной смеси давали нагреться до температуры окружающей среды. Через 1 час смесь охлаждали до 0^oC и осторожно гасили водой (0,4 мл). К данному раствору медленно добавляли гидроксид натрия (1,2 мл 15% по массе водного раствора) с последующим добавлением воды (0,4 мл). После перемешивания в течение 30 минут смесь фильтровали и твердые вещества тщательно промывали ТГФ, фильтрат концентрировали, что давало 1,71 г (93%) желательного продукта в виде белой пены, которую использовали без дальнейшей очистки: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,34 (д, J = 8,5 Гц, 2H), 7,20-7,30 (м, 3H), 6,80-6,90 (м, 4H), 6,73 (с, 1H), 6,55 (м, 1H), 5,88 (с, 1H), 4,06 (т, J = 6,3 Гц, 2H), 3,81 (с, 3H), 3,76 (с, 3H), 2,85-3,00 (м, 4H), 2,75-2,85 (м, 4H), 2,63-2,75 (м, 2H), 2,95 (м, 1H), 1,60-1,75 (м, 8H); Анал. расч. для: C 77,16; H 7,65; N 2,73. Найдено: C 77,33; H 7,79; N 2,71. МС (FD) m/e 513 (M+).

To a suspension of lithium aluminum hydride (0.3 g, 7.2 mmol) stirred at 0 ^° C. in THF (40 ml) was slowly added a solution of the product to obtain 11 (1.8 g, 3.6 mmol) in THF (25 ml ) for a 5 minute period of time. The reaction mixture was allowed to warm to ambient temperature. After 1 hour, the mixture was cooled to 0 ^° C. and carefully quenched with water (0.4 ml). Sodium hydroxide (1.2 ml of a 15% by weight aqueous solution) was slowly added to this solution, followed by the addition of water (0.4 ml). After stirring for 30 minutes, the mixture was filtered and the solids washed thoroughly with THF, the filtrate was concentrated to give 1.71 g (93%) of the desired product as a white foam, which was used without further purification: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.34 (d, J = 8.5 Hz, 2H), 7.20-7.30 (m, 3H), 6.80-6.90 (m, 4H), 6.73 (s , 1H), 6.55 (m, 1H), 5.88 (s, 1H), 4.06 (t, J = 6.3 Hz, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 2.85-3.00 (m, 4H), 2.75-2.85 (m, 4H), 2.63-2.75 (m, 2H), 2.95 (m , 1H); 1.60-1.75 (m, 8H); Anal calc. for: C, 77.16; H 7.65; N, 2.73. Found: C, 77.33; H 7.79; N 2.71. MS (FD) m / e 513 (M +).

 Example 26

 The hydrochloric acid salt of [2- (4-Methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-hexamethyleneiminyl) ethoxy] phenyl] methane.

К раствору продукта по примеру 25 (1,7 г, 3,3 ммоль), перемешиваемому в этилацетате (100 мл) при температуре окружающей среды, добавляли соляную кислоту (100 мл насыщенного раствора в этилацетате). Полученную смесь концентрировали, что давало 1,66 г (94%) желательного продукта, который использовали без очистки: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,48 (т, J = 8,9 Гц, 2H), 7,43 (д, J = 8,6 Гц, 1H), 7,20-7,35 (м, 3H), 7,10 (м, 1H), 6,85-7,00 (м, 4H), 6,75 (д, J = 8,6 Гц, 2H), 4,45-4,60 (м, 2H), 4,37 (с, 2H), 3,94 (с, 3H), 3,85 (с, 3H), 3,55-3,70 (м, 2H), 3,40-3,50 (м, 2H), 3,00-3,20 (м, 2H), 2,10-2,25 (м, 2H), 1,80-2,00 (м, 4H), 1,60-1,80 (м, 2H); ¹³C-ЯМР (75 МГц, ДМСО) δ 155,6, 137,15, 134,29, 134,19, 134,08, 132,29, 130,15, 129,01, 128,79, 127,28, 126,91, 125,95, 124,94, 118,63, 114,61, 113,70, 106,79, 62,42, 55,20, 55,13, 55,10, 54,85, 54,10, 33,77, 30,44, 26,05, 22,72; Анал. расч. для: C 74,49; H 7,20; N 2,63. Получ: C 74,73; H 7,16; N 2,62; МС (FD) m/e 495 (M+ - соляная кислота); ИК (KBr) 2234,10, 2862,73, 2835,72, 2448,94, 1624,27, 1608,84, 1511,42 см^-1.

To a solution of the product of Example 25 (1.7 g, 3.3 mmol) stirred in ethyl acetate (100 ml) at ambient temperature was added hydrochloric acid (100 ml of a saturated solution in ethyl acetate). The resulting mixture was concentrated to give 1.66 g (94%) of the desired product, which was used without purification: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.48 (t, J = 8.9 Hz, 2H), 7.43 (d, J = 8.6 Hz, 1H), 7.20-7.35 (m, 3H), 7.10 (m, 1H), 6.85-7.00 (m, 4H) 6.75 (d, J = 8.6 Hz, 2H), 4.45-4.60 (m, 2H), 4.37 (s, 2H), 3.94 (s, 3H), 3, 85 (s, 3H), 3.55-3.70 (m, 2H), 3.40-3.50 (m, 2H), 3.00-3.20 (m, 2H), 2.10- 2.25 (m, 2H), 1.80-2.00 (m, 4H), 1.60-1.80 (m, 2H); ¹³ C-NMR (75 MHz, DMSO) δ 155.6, 137.15, 134.29, 134.19, 134.08, 132.29, 130.15, 129.01, 128.79, 127.28 , 126.91, 125.95, 124.94, 118.63, 114.61, 113.70, 106.79, 62.42, 55.20, 55.13, 55.10, 54.85, 54 10, 33.77, 30.44, 26.05, 22.72; Anal calc. for: C 74.49; H 7.20; N, 2.63. Receive: C 74.73; H 7.16; N 2.62; MS (FD) m / e 495 (M + - hydrochloric acid); IR (KBr) 2234.10, 2862.73, 2835.72, 2448.94, 1624.27, 1608.84, 1511.42 cm ^-1 .

 Example 27

 [2- (4-Hydroxyphenyl) -6-hydroxy-naphthalen-1-yl] [4- [2- (1-hexamethyleneiminyl) ethoxy] phenyl] methane.

К раствору продукта по примеру 26 (1,3 г, 2,4 ммоль), перемешиваемому в 1,2-дихлорэтане (30 мл) при 0^oC, добавляли трихлорид бора (10 мл, 117 ммоль). Полученный темно-пурпурный раствор перемешивали в течение ночи при температуре окружающей среды в герметичной пробирке, затем охлаждая до 0^oC. Метанол (25 мл) медленно добавляли в течение 30-минутного промежутка времени (осторожно: выделение газа) и полученный раствор концентрировали. Неочищенный продукт растворяли в 20% метаноле/хлороформе и впоследствии промывали насыщенным бикарбонатом натрия и насыщенным раствором соли. Органический экстракт сушили (сульфат натрия), фильтровали и концентрировали. Полученную коричневую пену очищали методом радиальной хроматографии (градиент этилацетата/триэтиламина/метанола/гексана), что давало желто-коричневое твердое вещество. Данный продукт растворяли в этилацетате, затем промывали насыщенным бикарбонатом натрия. Органический экстракт концентрировали, что давало 0,60 г (54%) желательного продукта в виде белой пены: ¹H-ЯМР (300 МГц, ДМСО-d₆) δ 9,64 (с, 1H), 9,41 (с, 1H), 7,55-7,70 (м, 2H), 7,24 (д, J = 8,5 Гц, 1H), 7,00-7,10 (м, 3H), 6,95 (м, 1H), 6,81 (д, J = 8,6 Гц, 2H), 6,70-6,78 (м, 4H), 4,23 (с, 2H), 3,91 (т, J = 6,0 Гц, 2H), 2,70-2,80 (м, 2H), 2,55-2,70 (м, 4H), 1,40-1,60 (м, 8H); Анал. расч. для: C 79,63; H 7,11; N 2,99. Получ: C 79,35; H 6,87; N 2,75; МС (FD) m/e 468 (M+); ИК (KBr) 3362,35, 2926,39, 2855,98, 1734,23, 1704,33, 1610,77, 1509,49 см^-1.

Boron trichloride (10 ml, 117 mmol) was added to a solution of the product of Example 26 (1.3 g, 2.4 mmol) stirred in 1,2-dichloroethane (30 ml) at 0 ^° C. The resulting dark purple solution was stirred overnight at ambient temperature in a sealed tube, then cooled to 0 ^° C. Methanol (25 ml) was slowly added over a 30 minute period (carefully: gas evolution) and the resulting solution was concentrated. The crude product was dissolved in 20% methanol / chloroform and subsequently washed with saturated sodium bicarbonate and brine. The organic extract was dried (sodium sulfate), filtered and concentrated. The resulting brown foam was purified by radial chromatography (gradient of ethyl acetate / triethylamine / methanol / hexane) to give a tan solid. This product was dissolved in ethyl acetate, then washed with saturated sodium bicarbonate. The organic extract was concentrated to give 0.60 g (54%) of the desired product as a white foam: ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.64 (s, 1H), 9.41 (s, 1H), 7.55-7.70 (m, 2H), 7.24 (d, J = 8.5 Hz, 1H), 7.00-7.10 (m, 3H), 6.95 (m , 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.70-6.78 (m, 4H), 4.23 (s, 2H), 3.91 (t, J = 6.0 Hz, 2H), 2.70-2.80 (m, 2H), 2.55-2.70 (m, 4H), 1.40-1.60 (m, 8H); Anal calc. for: C 79.63; H 7.11; N, 2.99. Receive: C 79.35; H 6.87; N, 2.75; MS (FD) m / e 468 (M +); IR (KBr) 3362.35, 2926.39, 2855.98, 1734.23, 1704.33, 1610.77, 1509.49 cm ^-1 .

 Getting 12.

 [3,4-Dihydro-2- (4-methoxyphenyl) -3,4-dihydro-6-methoxynaphthalen-1-yl] [4- [2- (1-morpholinyl) ethoxy] phenyl] methanone.

Реакция продукта по получению 10 (2,1 г, 4,3 ммоль) морфолина (1,13 мл, 12,9 ммоль) и карбоната калия (1,78 г, 12,9 ммоль) в ДМФ (50 мл) в соответствии с методикой по получению 11 давала 80% выход желательного продукта в виде густой маслянистой жидкости: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,83 (д, J = 8,7 Гц, 2H), 7,60 (м, 1H), 7,20 (д, J = 8,8 Гц, 2H), 6,88 (д, J = 8,7 Гц, 1H), 6,65-6,80 (м, 5H), 4,05-4,20 (м, 2H), 3,80 (с, 3H), 3,73 (с, 3H), 3,70-3,80 (м, 4H), 2,90 (т, J = 7,9 Гц, 2H), 2,75-2,85 (м, 4H), 2,50-2,60 (м, 4H); МС (FD) m/e 499 (M+); анал. расч. для: C 74,53; H 6,66; N 2,80. Получ: C 74,75; H 6,58; N 2,83.

The reaction of the product to obtain 10 (2.1 g, 4.3 mmol) of morpholine (1.13 ml, 12.9 mmol) and potassium carbonate (1.78 g, 12.9 mmol) in DMF (50 ml) in accordance with the procedure for obtaining 11 gave 80% yield of the desired product in the form of a thick oily liquid: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.83 (d, J = 8.7 Hz, 2H), 7.60 (m , 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.7 Hz, 1H), 6.65-6.80 (m, 5H), 4 05-4.20 (m, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 3.70-3.80 (m, 4H), 2.90 (t, J = 7.9 Hz, 2H), 2.75-2.85 (m, 4H), 2.50-2.60 (m, 4H); MS (FD) m / e 499 (M +); anal calc. for: C 74.53; H 6.66; N, 2.80. Receive: C 74.75; H 6.58; N, 2.83.

 Getting 13.

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1- (3,3-dimethyl) pyrrolidinyl) ethoxy] phenyl] methanone.

Реакция продукта по получению 10 (2,1 г, 4,3 ммоль), 3,3-диметилпирролидина (1,2 мл, 12 ммоль) и карбоната калия (1,8 г, 13 ммоль) в ДМФ (100 мл) в соответствии с методикой по получению 11 давала 60% выход желательного продукта в виде густой маслянистой жидкости: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,80 (д, J = 8,7 Гц, 2H), 7,18 (д, J = 8,7 Гц, 2H), 6,87 (д, J = 8,6 Гц, 1H), 6,73-6,80 (м, 3H), 6,67 (д, J = 8,6 Гц, 2H), 6,60 (м, 1H), 4,05 (м, 2H), 3,78 (с, 3H), 3,71 (с, 3H), 2,89-3,05 (м, 2H), 2,73-2,86 (м, 4H), 2,64-2,75 (м, 2H), 2,04 (с, 2H), 1,60 (т, J = 6,9 Гц, 2H), 1,07 (с, 6H); МС (FD) m/e 511 (M+).

The reaction of the product to obtain 10 (2.1 g, 4.3 mmol), 3,3-dimethylpyrrolidine (1.2 ml, 12 mmol) and potassium carbonate (1.8 g, 13 mmol) in DMF (100 ml) in accordance with the procedure for obtaining 11 gave 60% yield of the desired product in the form of a thick oily liquid: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.7 Hz, 2H), 7.18 ( d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.6 Hz, 1H), 6.73-6.80 (m, 3H), 6.67 (d, J = 8 6Hz, 2H), 6.60 (m, 1H), 4.05 (m, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 2.89-3.05 (m, 2H), 2.73-2.86 (m, 4H), 2.64-2.75 (m, 2H), 2.04 (s, 2H), 1.60 (t, J = 6 9 Hz, 2H); 1.07 (s, 6H); MS (FD) m / e 511 (M +).

 Example 28

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-morpholinyl) ethoxy] phenyl] methanol.

Реакция продукта по получению 12 (1,6 г, 3,2 ммоль) с литийалюминийгидридом (0,3 г, 7,2 ммоль) в ТГФ (65 мл) в соответствии с методикой примера 25 давала 98% выход желательного продукта в виде белой пены: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,39 (д, J = 8,7 Гц, 2H), 7,20-7,30 (м, 4H), 6,80-7,00 (м, 3H), 6,73 (м, 1H), 6,55 (м, 1H), 5,86 (д, J = 4,2 Гц, 1H), 4,09 (т, J = 5,6 Гц, 2H), 3,80 (с, 3H), 3,70-3,80 (м, 4H), 3,76 (с, 3H), 2,85-3,00 (м, 2H), 2,75-2,85 (м, 2H), 2,65 (м, 1H), 2,55-2,65 (м, 4H), 1,05-1,10 (м, 2H); МС (FD) m/e 501 (M+); Анал. расч. для: C 74,23; H 7,03; N 2,79. Найдено: C 74,51; H 7,18; N 2,79.

The reaction of the product to obtain 12 (1.6 g, 3.2 mmol) with lithium aluminum hydride (0.3 g, 7.2 mmol) in THF (65 ml) in accordance with the procedure of example 25 gave 98% yield of the desired product as white foam: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.39 (d, J = 8.7 Hz, 2H), 7.20-7.30 (m, 4H), 6.80-7.00 (m, 3H), 6.73 (m, 1H), 6.55 (m, 1H), 5.86 (d, J = 4.2 Hz, 1H), 4.09 (t, J = 5, 6 Hz, 2H), 3.80 (s, 3H), 3.70-3.80 (m, 4H), 3.76 (s, 3H), 2.85-3.00 (m, 2H), 2.75-2.85 (m, 2H), 2.65 (m, 1H), 2.55-2.65 (m, 4H), 1.05-1.10 (m, 2H); MS (FD) m / e 501 (M +); Anal calc. for: C 74.23; H 7.03; N, 2.79. Found: C, 74.51; H 7.18; N, 2.79.

 Example 29

 [3,4-Dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1- (3,3-dimethyl) pyrrolidinyl) ethoxy] phenyl] methanol.

Реакция продукта по получению 13 (1,3 г, 2,5 ммоль) с литийалюминийгидридом (0,2 г, 5,0 ммоль) в ТГФ (65 мл) в соответствии с методикой примера 25 давала 98% выход желательного продукта в виде белой пены:: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,33 (д, J = 8,6 Гц, 2H), 7,20-7,30 (м, 3H), 6,80-6,90 (м, 4H), 6,70 (м, 1H), 6,52 (м, 1H), 5,85 (с, 1H), 4,04 (т, J = 6,1 Гц, 2H), 3,79 (с, 3H), 3,74 (с, 3H), 2,80-2,95 (м, 4H), 2,60-2,75 (м, 4H), 2,42 (с, 2H), 2,20 (м, 1H), 1,85 (м, 1H), 1,61 (м, 1H), 1,08 (с, 6H); МС (FD) m/e 513 (M+); Анал. расч. для: C 77,16; H 7,65; N 2,73. Найдено: C 77,33; H 7,51; N 2,69.

The reaction of the product to obtain 13 (1.3 g, 2.5 mmol) with lithium aluminum hydride (0.2 g, 5.0 mmol) in THF (65 ml) in accordance with the procedure of example 25 gave 98% yield of the desired product as white foam :: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.33 (d, J = 8.6 Hz, 2H), 7.20-7.30 (m, 3H), 6.80-6, 90 (m, 4H), 6.70 (m, 1H), 6.52 (m, 1H), 5.85 (s, 1H), 4.04 (t, J = 6.1 Hz, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 2.80-2.95 (m, 4H), 2.60-2.75 (m, 4H), 2.42 (s, 2H), 2.20 (m, 1H), 1.85 (m, 1H), 1.61 (m, 1H), 1.08 (s, 6H); MS (FD) m / e 513 (M +); Anal calc. for: C, 77.16; H 7.65; N, 2.73. Found: C, 77.33; H 7.51; N, 2.69.

 Example 30

 [2- (4-Methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-morpholinyl) ethoxy] phenyl] methane hydrochloride.

Реакция продукта по примеру 28 (1,58 г, 3,1 ммоль) с соляной кислотой (100 мл насыщенного раствора в этилацетате) в этилацетате (100 мл) в соответствии с методикой примера 26 давала 94% выход желательного продукта в виде белой пены: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,70-7,85 (м, 2H), 7,44 (д, J = 8,4 Гц, 1H), 7,20-7,40 (м, 4H), 6,86-7,15 (м, 4H), 6,70-6,86 (м, 2H), 4,50-4,65 (м, 2H), 4,25-4,50 (м, 4H), 3,83-4,10 (м, 2H), 2,94 (с, 3H), 3,85 (с, 3H), 3,50-3,70 (м, 2H), 3,40-3,50 (м, 2H), 3,00-3,20 (м, 2H); МС (FD) m/e 483 (M+ - соляная кислота).

The reaction of the product of example 28 (1.58 g, 3.1 mmol) with hydrochloric acid (100 ml of a saturated solution in ethyl acetate) in ethyl acetate (100 ml) in accordance with the procedure of example 26 gave 94% yield of the desired product as a white foam: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.70-7.85 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.20-7.40 (m , 4H), 6.86-7.15 (m, 4H), 6.70-6.86 (m, 2H), 4.50-4.65 (m, 2H), 4.25-4.50 (m, 4H), 3.83-4.10 (m, 2H), 2.94 (s, 3H), 3.85 (s, 3H), 3.50-3.70 (m, 2H), 3.40-3.50 (m, 2H); 3.00-3.20 (m, 2H); MS (FD) m / e 483 (M + - hydrochloric acid).

 Example 31

 [2- (4-Methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1- (3,3-dimethyl) pyrrolidinyl) ethoxy] phenyl] methane hydrochloride.

Реакция продукта по примеру 29 (1,2 г, 2,4 ммоль) с соляной кислотой (100 мл насыщенного раствора в этилацетате) в этилацетате (100 мл) в соответствии с методикой примера 26 давала 92% выход желательного продукта в виде белой пены: ¹H-ЯМР (300 МГц, CDCl₃) δ 7,29 (т, J = 9,3 Гц, 2H), 7,41 (д, J = 8,2 Гц, 1H), 7,15-7,30 (м, 3H), 7,19 (д, J = 6,8 Гц, 1H), 6,85-7,00 (м, 4H), 6,73 (д, J = 7,52 Гц, 2H), 4,48 (с, 2H), 4,35 (с, 2H), 3,93 (с, 3H), 3,83 (с, 3H), 3,60 (м, 1H), 3,15-3,50 (м, 2H), 3,15 (м, 1H), 2,76 (м, 1H), 2,05 (м, 1H), 1,85 (м, 1H), 1,75 (м, 1H), 1,33 (с, 3H), 1,33 (с, 3H); МС (FD) m/e 495 (M+ - соляная кислота); Анал. расч. для: C 74,49; H 7,20; N 2,63. Найдено: C 74,70; H 7,18; N 2,47.

The reaction of the product of example 29 (1.2 g, 2.4 mmol) with hydrochloric acid (100 ml of a saturated solution in ethyl acetate) in ethyl acetate (100 ml) in accordance with the procedure of example 26 gave 92% yield of the desired product as a white foam: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.29 (t, J = 9.3 Hz, 2H), 7.41 (d, J = 8.2 Hz, 1H), 7.15-7, 30 (m, 3H), 7.19 (d, J = 6.8 Hz, 1H), 6.85-7.00 (m, 4H), 6.73 (d, J = 7.52 Hz, 2H ), 4.48 (s, 2H), 4.35 (s, 2H), 3.93 (s, 3H), 3.83 (s, 3H), 3.60 (m, 1H), 3.15 -3.50 (m, 2H), 3.15 (m, 1H), 2.76 (m, 1H), 2.05 (m, 1H), 1.85 (m, 1H), 1.75 ( m, 1H), 1.33 (s, 3H), 1.33 (s, 3H); MS (FD) m / e 495 (M + - hydrochloric acid); Anal calc. for: C 74.49; H 7.20; N, 2.63. Found: C, 74.70; H 7.18; N, 2.47.

 Example 32

 [2- (4-Hydroxyphenyl) -6-hydroxy-naphthalen-1-yl] [4- [2- (1-morpholinyl) ethoxy] phenyl] methane.

Реакция продукта по примеру 30 (1,28 г, 2,40 ммоль) с трихлоридом бора (10 мл, 117 ммоль) в 1,2-дихлорэтане (30 мл) в соответствии с методикой примера 27 давала 28% выход желательного продукта в виде белого твердого вещества: ИК (KBr) 3317,99, 2927,35, 2868,51, 1610,77, 1509,49 см^-1; ¹H-ЯМР (300 МГц, CDCl₃) δ 7,75 (д, J = 9,3 Гц, 1H), 7,55 (м, 1H), 7,37 (д, J = 8,5 Гц, 1H), 7,10-7,20 (м, 2H), 6,65-7,05 (м, 8H), 5,50 (ушир. с, 2H), 4,32 (с, 2H), 4,00-4,20 (м, 2H), 3,70-3,80 (м, 4H), 2,70-2,85 (м, 2H), 2,50-2,70 (м, 4H); МС (FD) m/e 456 (M+); Анал. расч. для: C 76,46; H 6,42; N 3,07. Получ: C 76,75; H 6,44; N 3,02.

The reaction of the product of example 30 (1.28 g, 2.40 mmol) with boron trichloride (10 ml, 117 mmol) in 1,2-dichloroethane (30 ml) in accordance with the procedure of example 27 gave 28% yield of the desired product as white solid: IR (KBr) 3317.99, 2927.35, 2868.51, 1610.77, 1509.49 cm ^-1 ; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.75 (d, J = 9.3 Hz, 1H), 7.55 (m, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.10-7.20 (m, 2H), 6.65-7.05 (m, 8H), 5.50 (br s, 2H), 4.32 (s, 2H), 4 , 00-4.20 (m, 2H), 3.70-3.80 (m, 4H), 2.70-2.85 (m, 2H), 2.50-2.70 (m, 4H) ; MS (FD) m / e 456 (M +); Anal calc. for: C 76.46; H 6.42; N, 3.07. Receive: C 76.75; H 6.44; N, 3.02.

 Example 33

 [2- (4-Hydroxyphenyl) -6-hydroxy-naphthalen-1-yl] [4- [2- (1- (3,3-dimethyl) pyrrolidinyl) ethoxy] phenyl] methane.

Реакция продукта по примеру 31 (1,2 г, 2,3 ммоль) с трихлоридом бора (10 мл, 117 ммоль) в 1,2-дихлорэтане (30 мл) в соответствии с методикой примера 27 давала 58% выход желательного продукта в виде белого твердого вещества: ИК (KBr) 3370,07, 2955,32, 2869,48, 1711,08, 1610,77, 1510,46 см^-1; ¹H-ЯМР (300 МГц, CDCl₃) δ 7,71 (д, J = 9,2 Гц, 1H), 7,56 (д, J = 8,5 Гц, 1H), 7,32 (д, J = 8,4 Гц, 1H), 7,10-7,15 (м, 3H), 6,98 (м, 1H), 6,75-6,85 (м, 4H), 6,58 (д, J = 8,5 Гц, 2H), 4,28 (с, 2H), 4,11 (т, J = 7,70 Гц, 2H), 2,90 (т, J = 5,9 Гц, 2H), 2,82 (т, J = 6,7 Гц, 2H), 2,79 (т, J = 6,7 Гц, 2H), 1,66 (т, J = 6,9 Гц, 2H), 1,10 (с, 6H); МС (FD) m/e 468 (M+); Анал. расч. для: C 79,63; H 7,11; N 3,00. Получ: C 79,65; H 7,24; N 2,72.

The reaction of the product of example 31 (1.2 g, 2.3 mmol) with boron trichloride (10 ml, 117 mmol) in 1,2-dichloroethane (30 ml) in accordance with the procedure of example 27 gave 58% yield of the desired product as white solid: IR (KBr) 3370.07, 2955.32, 2869.48, 1711.08, 1610.77, 1510.46 cm ^-1 ; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.71 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.10-7.15 (m, 3H), 6.98 (m, 1H), 6.75-6.85 (m, 4H), 6.58 (d , J = 8.5 Hz, 2H), 4.28 (s, 2H), 4.11 (t, J = 7.70 Hz, 2H), 2.90 (t, J = 5.9 Hz, 2H ), 2.82 (t, J = 6.7 Hz, 2H), 2.79 (t, J = 6.7 Hz, 2H), 1.66 (t, J = 6.9 Hz, 2H), 1.10 (s, 6H); MS (FD) m / e 468 (M +); Anal calc. for: C 79.63; H 7.11; N, 3.00. Receive: C 79.65; H 7.24; N 2.72.

 Getting 14.

 [2- (4-Methoxyphenyl) -6-methoxynaphthalen-1-yl] [4-methoxyphenyl) methanone.

К 50 мл диоксана добавляли 6,0 г (15 ммоль) [3,4-дигидро-2-(4-метоксифенил)-6-метоксинафталин-1-ил] (4- метоксифенил)метанона и 7,3 г (32 ммоль) 2,3-дихлор-5,6-дициано-1,4-бензохинона. Смесь нагревали с обратным холодильником в течение 2 часов, затем оставляли перемешиваться при температуре окружающей среды в течение 60 часов. Смесь затем концентрировали досуха и остаток помещали в 500 мл метиленхлорида и трижды промывали 400 мл 2Н гидрохлорида натрия с последующим однократным промыванием 500 мл деионированной воды. Полученный органический слой отделяли, сушили над сульфатом натрия и растворитель удаляли под вакуумом. Полученный продукт затем очищали методом флэш-хроматографии (силикагель, градиент 20% этилацетат/гексана), что давало выход 4,75 г (80%)а соединения заголовка в виде белой пены: ЯМР QE300 МГЦ в CDCl₃: (3,80 ч/м, с, 3H), (4,00 ч/с, с, 3H), (6,75 ч/м, д, 2H), (7,20 ч/м, дд, 1H), (7,30 ч/м, дс, 1H), (7,40 ч/м, д, 2H), (7,60 ч/м, д, 1H), (7,75 ч/м, д, 2H), (7,95 ч/м, д, 1H). МС (FD) me/e 398 (M+); Анал. расч. для: C 78,37; H 5,57. Получ: C 78,55; H 5,78.

6.0 g (15 mmol) of [3,4-dihydro-2- (4-methoxyphenyl) -6-methoxynaphthalen-1-yl] (4-methoxyphenyl) methanone and 7.3 g (32 mmol) were added to 50 ml of dioxane. ) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The mixture was heated under reflux for 2 hours, then allowed to mix at ambient temperature for 60 hours. The mixture was then concentrated to dryness and the residue was taken up in 500 ml of methylene chloride and washed three times with 400 ml of 2N sodium hydrochloride, followed by a single wash with 500 ml of deionized water. The resulting organic layer was separated, dried over sodium sulfate and the solvent was removed in vacuo. The resulting product was then purified by flash chromatography (silica gel, gradient 20% ethyl acetate / hexane) to give 4.75 g (80%) of the title compound as a white foam: NMR QE300 MHZ in CDCl ₃ : (3.80 h / m, s, 3H), (4.00 ppm, s, 3H), (6.75 ppm, d, 2H), (7.20 ppm, dd, 1H), (7, 30 ppm, ds, 1H), (7.40 ppm, d, 2H), (7.60 ppm, d, 1H), (7.75 ppm, d, 2H), ( 7.95 ppm, d, 1H). MS (FD) me / e 398 (M +); Anal calc. for: C 78.37; H 5.57. Receive: C 78.55; H 5.78.

 Example 34

 [2- (4-Methoxyphenyl) -6-methoxynaphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methane hydrochloride.

К 20 мл пропилбензола добавляли 240 мг (6,01 ммоль) 95% литийалюминийгидрида и 240 мг (0,484 ммоль) соединения по получению 14. Смесь нагревали с обратным холодильником в течение 35 минут и давали остыть до температуры окружающей среды. К смеси осторожно добавляли 1 мл деионированной воды с последующим добавлением 3 мл 15% гидроксида натрия/деионированной воды (по массе) и затем еще 1 мл деионированной воды. Смесь перемешивали в течение 15 минут при температуре окружающей среды и осадок удаляли с помощью вакуум-фильтра. Маточный раствор разбавляли метиленхлоридом (100 мл), однократно промывали насыщенным раствором соли, сушили над сульфатом натрия и сушили на роторном испарителе досуха. Коричневое клейкое вещество очищали по методу радиальной хроматографии на 4 мм пластинке и 19:1 метиленхлориде:метаноле в качестве элюента, что давало соединение заголовка. ЯМР QE300 МГц в CDCl₃: (1,55 ч/м, м, 2H), (1,75 ч/м, сложный, 4H), (2,60 ч/м, сложный, 4H), (2,85 ч/м, т, 2H), (3,95 ч/м, с, 3H), (4,05 ч/м, с, 3H), (4,20 ч/м, т, 2H), (4,45 ч/м, с, 2H), (6,85 ч/м, д, 2H), (7,00 ч/м, сложный, 4H), (7,15 ч/м, дд, 1H), (7,25 ч/м, дс, 1H), (7,35 ч/м, д, 2H), (7,50 ч/м, д, 1H), ), (7,80 ч/м, д, 1H), (7,90 ч/м, д, 1H), МС (FD) me/e 481 (M+).

To 20 ml of propylbenzene was added 240 mg (6.01 mmol) of 95% lithium aluminum hydride and 240 mg (0.484 mmol) of the compound of Preparation 14. The mixture was heated under reflux for 35 minutes and allowed to cool to ambient temperature. 1 ml of deionized water was carefully added to the mixture, followed by 3 ml of 15% sodium hydroxide / deionized water (by weight) and then another 1 ml of deionized water. The mixture was stirred for 15 minutes at ambient temperature and the precipitate was removed using a vacuum filter. The mother liquor was diluted with methylene chloride (100 ml), washed once with brine, dried over sodium sulfate and dried on a rotary evaporator to dryness. The brown adhesive was purified by radial chromatography on a 4 mm plate and 19: 1 methylene chloride: methanol as eluent, which afforded the title compound. NMR QE300 MHz in CDCl ₃ : (1.55 ppm, m, 2H), (1.75 ppm, complex, 4H), (2.60 ppm, complex, 4H), (2.85 ppm, t, 2H), (3.95 ppm, s, 3H), (4.05 ppm, s, 3H), (4.20 ppm, t, 2H), (4 , 45 ppm, s, 2H), (6.85 ppm, d, 2H), (7.00 ppm, complex, 4H), (7.15 ppm, dd, 1H), (7.25 ppm, ds, 1H), (7.35 ppm, d, 2H), (7.50 ppm, d, 1H),), (7.80 ppm, d , 1H), (7.90 ppm, d, 1H), MS (FD) me / e 481 (M +).

 Example 35

 [2- (4-Hydrophenyl) -6-hydroxynaphthalen-1-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] methane.

К суспензии лишенного защиты продукта по получению 12, где такое лишение защиты осуществляют по стандартным методикам, как описано здесь, (0,51 г, 1,00 ммоль), перемешиваемому в n-пропилбензоле, добавляют Red-Al® (0,87 г, 6,00 ммоль) и смесь нагревают с обратным холодильником. Через 3 часа раствор охлаждают до температуры окружающей среды и осторожно гасят 1,0 Н соляной кислотой. Полученную двухфазную смесь экстрагируют добавлением этилацетата и объединенные органические экстракты промывают насыщенным
водным бикарбонатом, насыщенным раствором соли, сушат (MgSO₄), фильтруют и концентрируют. Очистка сырого продукта методом радиальной хроматографии (силикагель, этилацетат/гексаны/метанол/триэтиламин 2,5/2,5/0,7/0,3) дает продукт заголовка.

Red-Al® (0.87 g) is added to the suspension of the unprotected product of Preparation 12, where such deprotection is carried out according to standard procedures as described herein (0.51 g, 1.00 mmol), stirred in n-propylbenzene. , 6.00 mmol) and the mixture is heated under reflux. After 3 hours, the solution was cooled to ambient temperature and carefully quenched with 1.0 N hydrochloric acid. The resulting biphasic mixture was extracted with ethyl acetate and the combined organic extracts washed with saturated
aqueous bicarbonate, brine, dried (MgSO ₄ ), filtered and concentrated. Purification of the crude product by radial chromatography (silica gel, ethyl acetate / hexanes / methanol / triethylamine 2.5 / 2.5 / 0.7 / 0.3) gives the title product.

 Testing Methodology.

 General method of obtaining.

 In the examples illustrating the methods, a postmenopausal model was used in which the uterus responded to various courses of treatment.

Charles River Laboratories (Portage, MI) obtained 75 old female Sprague Dawley rats (weighing 200 to 250 g). Animals underwent bilateral ovariectomy (OVE) at Charles River Laboratories and were sent after one week. Upon receipt, they were placed in metal suspension cells and had ad libitum access to food (0.5% calcium) and water for one week. The room temperature was maintained at 22.2 ± 1.7 ^o C with a minimum relative humidity of 40%. The light mode in the room consisted of 12 light hours and 12 dark hours. The experimental groups ranged from 5 to 6 rats.

Tissue selection according to the schemes of drug administration. After a one-week acclimatization period (thus, two weeks after EIA), daily doses of the test compound were started. Test compounds were administered subcutaneously as a suspension in 20% β-hydroxycyclodextrin. Doses were administered orally to animals for 4 days. During the drug administration schedule, animals were weighed and anesthetized with a mixture of ketamine: xylazine (2: 1, by volume) and a blood sample was taken using cardiac puncture. Animals were sacrificed by strangulation with CO ₂ , the uterus was removed through a midline incision, and the fresh weight of the uterus was determined.

 Inhibition of uterine tamoxifen stimulation in rats using a compound of formula I.

The data presented in table 1 show comparative results in rats after ovariectomy (treated with only 20% cyclodextrin), rats treated with 0.01, 0.1, 1.0 and 10.0 mg / kg of tamoxifen, and rats, treated with the same doses of tamoxifen plus 0.1, 1.0 and 10.0 mg / kg of a compound of formula I in which R ¹ and R ² are —OH and R ³ is 1-piperidinyl (“compound of formula I” in table 1).

 These data show that a compound of formula I, administered at a dose of 10 mg / kg together with tamoxifen, significantly suppresses the uterine stimulation effect of tamoxifen, especially when administered together with higher therapeutic doses of tamoxifen.

Claims (11)

1. The method of minimizing the hysterotrophic effect of non-steroidal antiestrogenic compounds of the formula II

where either R ⁴ is H or a lower alkyl radical and R ⁵ is a lower alkyl radical, or R ⁴ and R ^{5 are} attached to an adjacent nitrogen atom to form a heterocyclic radical;
R ⁶ is H or a lower alkyl radical;
R ⁷ is H, halogen, OH, a lower alkyl radical, or is a buta-1,3-dienyl radical, which together with the adjacent benzene ring forms a naphthyl radical;
R ⁸ is H or OH;
n is 2
or a pharmaceutically acceptable salt thereof, when said compound of formula II is administered to a woman for the treatment or prophylaxis of breast cancer, comprising simultaneously or sequentially administering to said woman a compound of formula I

where R ¹ represents —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl) or —OSO ₂ (C ₄ -C ₆ alkyl);
R ² is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl), or —OSO ₂ (C ₄ -C ₆ alkyl);
n is 2 or 3;
R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino or 1-hexamethyleneimino;
or a pharmaceutically acceptable salt thereof. 2. The method according to claim 1, where the specified compound of formula II is a compound where each of R ⁴ and R ⁵ is methyl; R ⁶ is ethyl; R ⁷ is H; R ⁸ is H; and n is 2, or a pharmaceutically acceptable salt thereof. 3. The method of claim 1, wherein said compound of formula I is a compound wherein each of R ¹ and R ² is —OH; R ³ is 1-piperidinyl; and n is 2, or a pharmaceutically acceptable salt thereof. 4. The method according to claim 2, wherein said compound of formula I is a compound wherein each of R ¹ and R ² is —OH; R ³ is 1-piperidinyl; and n is 2, or a pharmaceutically acceptable salt thereof.  5. The method according to claim 4, where the specified compound of formula I is its hydrochloric acid salt.  6. The method according to any one of claims 1 to 5, wherein said compound of formula I is administered simultaneously with administration of said compound of formula II.  7. The method according to any one of claims 1 to 5, wherein said compound of formula I is administered sequentially with respect to said compound of formula II. 8. A pharmaceutical composition comprising an effective amount of a first component, which is a compound of formula II

where either R ⁴ is H or a lower alkyl radical, and R ⁵ is a lower alkyl radical, or R ⁴ and R ^{5 are} attached to an adjacent nitrogen atom to form a heterocyclic radical;
R ⁶ is H or a lower alkyl radical;
R ⁷ represents H, halogen, OH, a lower alkyl radical or is a buta-1,3-dienyl radical, which together with the adjacent benzene ring forms a naphthyl radical;
R ⁸ is H or OH; and
n is 2
or a pharmaceutically acceptable salt thereof, when said first component is administered to a woman to treat or prevent breast cancer, and an effective amount of the second component, which is a compound of formula I

where R ¹ is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl) or —OSO ₂ (C ₄ -C ₆ alkyl);
R ² is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl) or —OSO ₂ (C ₄ -C ₆ alkyl);
n is 2 or 3; and
R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino or 1-hexamethyleneimino,
or a pharmaceutically acceptable salt thereof and said second component are administered to minimize the hysterotrophic effect induced by the compound of formula II, together with a pharmaceutically acceptable carrier, excipient or diluent. 9. The pharmaceutical composition of claim 8, wherein said compound of formula II is a compound wherein each of R ⁴ and R ⁵ is methyl; R ⁶ is ethyl; R ⁷ is H; R ⁸ is H; and n is 2, or a pharmaceutically acceptable salt thereof. 10. The pharmaceutical composition according to claim 9, wherein said compound of formula I is a compound wherein each of R ¹ and R ² is —OH; R ³ is 1-piperidinyl; and n is 2, or a pharmaceutically acceptable salt thereof.  11. The pharmaceutical composition according to any one of claims 8 to 10, wherein said pharmaceutically acceptable salt of a compound of formula I is a hydrochloric acid salt.

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